2022/11/02 更新

写真a

イシダ タカシ
石田 高司
ISHIDA Takashi
所属
大学院医学系研究科 総合医学専攻 微生物・免疫学 特任教授
職名
特任教授

学位 1

  1. 博士(医学) ( 2005年3月   名古屋市立大学 ) 

研究キーワード 2

  1. 腫瘍免疫学

  2. 血液内科学

研究分野 1

  1. ライフサイエンス / 血液、腫瘍内科学  / 腫瘍免疫学

経歴 6

  1. 名古屋大学大学院医学系研究科   分子細胞免疫学   特任教授

    2019年11月 - 現在

  2. 岩手医科大学   内科学講座血液腫瘍内科分野   教授

    2018年1月 - 2019年3月

  3. 名古屋市立大学   大学院医学研究科 輸血部/血液腫瘍内科学   准教授

    2012年7月 - 2017年12月

  4. 名古屋市立大学   大学院医学研究科 輸血部/血液腫瘍内科学   講師

    2007年7月 - 2012年6月

  5. 名古屋市立大学   大学院医学研究科 血液腫瘍内科学   助教

    2006年11月 - 2007年3月

  6. 名古屋市立大学   血液内科学   臨床研究医

    2005年4月 - 2006年10月

▼全件表示

学歴 2

  1. 名古屋市立大学   大学院医学研究科

    2001年4月 - 2005年3月

  2. 名古屋市立大学   医学部

    1990年4月 - 1996年3月

所属学協会 2

  1. 日本内科学会 (認定内科医、総合内科専門医、認定指導医)

  2. 日本輸血・細胞治療学会(認定医)

委員歴 6

  1. 日本内科学会   認定内科医、認定総合内科専門医、認定指導医  

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    団体区分:学協会

  2. 日本癌学会   評議員  

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    団体区分:学協会

  3. 愛知県合同輸血療法委員会   委員  

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    団体区分:自治体

  4. 愛知県 HTLV-1母子感染対策協議会   委員  

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    団体区分:自治体

  5. 日本血液学会 (認定専門医、認定指導医)   代議員  

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    団体区分:学協会

    日本血液学会 (認定専門医、認定指導医)

  6. 日本がん免疫学会   代議員  

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    団体区分:学協会

    日本がん免疫学会

▼全件表示

受賞 2

  1. 高松宮妃癌研究基金研究助成金

    2020年12月  

  2. 小林がん学術振興会 研究助成金

    2020年6月  

 

論文 228

  1. Mogamulizumab for adult T-cell leukemia-lymphoma: a multicenter prospective observational study 査読有り

    Yonekura Kentaro, Kusumoto Shigeru, Choi Ilseung, Nakano Nobuaki, Ito Asahi, Suehiro Youko, Imaizumi Yoshitaka, Yoshimitsu Makoto, Nosaka Kisato, Ohtsuka Eiichi, Hidaka Michihiro, Jo Tatsuro, Sasaki Hidenori, Moriuchi Yukiyoshi, Ogata Masao, Tatetsu Hiro, Ishitsuka Kenji, Miyazaki Yasushi, Ueda Ryuzo, Utsunomiya Atae, Ishida Takashi

    BLOOD ADVANCES   4 巻 ( 20 ) 頁: 5133 - 5145   2020年10月

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    担当区分:責任著者   記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blood Advances  

    Monitoring of Immune Responses Following Mogamulizumab-Containing Treatment in Patients with Adult T-Cell Leukemia-Lymphoma (ATL) (MIMOGA) is a multicenter prospective observational study to establish the most effective and safe treatment strategy using mogamulizumab for ATL patients (UMIN000008696). Mogamulizumab-naive patients were enrolled (n 5 102), of whom 101 received mogamulizumab-containing treatment (68 acute, 18 lymphoma, 12 chronic, and 3 smoldering subtypes). At enrollment, there was a significant inverse correlation between serum soluble interleukin-2 receptor (sIL-2R) levels and percentages of Tax-specific cytotoxic T lymphocytes (Tax-CTLs) in the entire lymphocyte population or in the CD81 T cell subset, but there was not a correlation with cytomegalovirus pp65–specific cytotoxic T lymphocytes (CMV-CTLs). The overall response rate was 65%, and median progression-free survival and overall survival (OS) were 7.4 and 16.0 months, respectively. A higher percentage of Tax-CTLs, but not CMV-CTLs, within the entire lymphocyte population or in the CD81 T cell subset was significantly associated with longer survival. Multivariate analysis identified the clinical subtype (acute or lymphoma type), a higher sIL-2R level, and a lower percentage of CD22CD191 B cells in peripheral blood mononuclear cells as significant independent unfavorable prognostic factors for OS. This indicates that a higher percentage of B cells might reflect some aspect of a favorable immune status leading to a good outcome with mogamulizumab treatment. In conclusion, the MIMOGA study has demonstrated that mogamulizumab exerts clinically meaningful antitumor activity in ATL. The patient’s immunological status before mogamulizumab was significantly associated with treatment outcome. Further time series immunological analyses, in addition to comprehensive genomic analyses, are warranted.

    DOI: 10.1182/bloodadvances.2020003053

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  2. Robust CD8(+) T-cell proliferation and diversification after mogamulizumab in patients with adult T-cell leukemia-lymphoma 査読有り 国際誌

    Saito Masato, Ishii Toshihiko, Urakawa Itaru, Matsumoto Asuka, Masaki Ayako, Ito Asahi, Kusumoto Shigeru, Suzuki Susumu, Takahashi Takeshi, Morita Akimichi, Inagaki Hiroshi, Iida Shinsuke, Ishida Takashi

    BLOOD ADVANCES   4 巻 ( 10 ) 頁: 2180 - 2191   2020年5月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blood Advances  

    Skin-related adverse events (AEs) occur frequently in adult T-cell leukemia-lymphoma (ATL) patients treated with mogamulizumab, a humanized anti-CCR4 monoclonal antibody. This study was undertaken to elucidate the mechanisms of mogamulizumab-induced skin-related AEs. We analyzed the T-cell receptor b chain repertoire in ATL patients' peripheral blood mononuclear cells (PBMCs) before and after mogamulizumab. Skin-related AEs were present in 16 patients and were absent in 8 patients. Additionally, we included 11 patients before and after chemotherapy without mogamulizumab. Immune-related gene expression in PBMCs before and after mogamulizumab was also assessed (n 5 24). Mogamulizumab treatment resulted in CCR41 T-cell depletion, and the consequent lymphopenia provoked homeostatic CD81 T-cell proliferation, as evidenced by increased expressions of CD8B and CD8A, which were significantly greater in patients with skin-related AEs than in those without them. We hypothesize that proliferation is driven by the engagement of self-antigens, including skin-related antigens, in the face of regulatory T-cell depletion. Together with the observed activated antigen presentation function, this resulted in T-cell diversification that was significantly greater in patients with skin-related AEs than in those without. We found that the CD81 T cells that proliferated and diversified after mogamulizumab treatment were almost entirely newly emerged clones. There was an inverse relationship between the degree of CCR41 T-cell depletion and increased CD81 T-cell proliferation and diversification. Thus, lymphocyte-depleting mogamulizumab treatment provokes homeostatic CD81 T-cell proliferation predominantly of newly emerging clones, some of which could have important roles in the pathogenesis of mogamulizumab-induced skin-related AEs.

    DOI: 10.1182/bloodadvances.2020001641

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  3. Mogamulizumab Treatment Elicits Autoantibodies Attacking the Skin in Patients with Adult T-Cell Leukemia-Lymphoma. 査読有り

    Suzuki Y, Saito M, Ishii T, Urakawa I, Matsumoto A, Masaki A, Ito A, Kusumoto S, Suzuki S, Hiura M, Takahashi T, Morita A, Inagaki H, Iida S, Ishida T

    Clinical cancer research : an official journal of the American Association for Cancer Research   25 巻 ( 14 ) 頁: 4388 - 4399   2019年

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Clinical Cancer Research  

    Purpose: The anti-CCR4 mAb, Mogamulizumab, offers (CDC) mediated by autoantibodies against keratinocytes or therapeutic benefit to patients with adult T-cell leukemia-melanocytes was proportionally related to the severity of the lymphoma (ATL), but skin-related adverse events (AE) such erythema multiforme. The presence of autoantibodies in the as erythema multiforme occur frequently. The purpose of this epidermis was confirmed in all biopsy specimens of Moga-study was to determine the mechanisms by which Mogamu-mulizumab-induced erythema multiforme (n ¼ 12). Further-lizumab causes skin-related AEs in patients with ATL. more, colocalization of autoantibodies and C1q, suggesting Experimental Design: We investigated whether autoanti-the activation of CDC, was observed in 67% (8/12). In bodies were present in patients' sera using flow cytometry to contrast, no autoantibody or C1q was found in ATL tumor determine binding to keratinocytes and melanocytes (n ¼ 17), skin lesions (n ¼ 13). Consistent with these findings, NGS and immunofluorescence analysis of tissue sections. We ana-demonstrated that IgM germline genes had newly emerged lyzed the IgM heavy chain repertoire in peripheral blood and expanded, resulting in IgM repertoire skewing at the time mononuclear cells before and after Mogamulizumab or other of erythema multiforme. chemotherapy by next-generation sequencing (NGS; n ¼ 16). Conclusions: Mogamulizumab elicits autoantibodies play-Results: Autoantibodies recognizing human keratinocytes ing an important role in skin-related AEs, possibly associated or melanocytes were found in the sera of 6 of 8 patients with regulatory T-cell depletion. This is the first report dem-suffering from Mogamulizumab-induced erythema multi-onstrating the presence of skin-directed autoantibodies after forme. In one patient, complement-dependent cytotoxicity Mogamulizumab treatment.

    DOI: 10.1158/1078-0432.CCR-18-2575

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  4. CCR4 mutations associated with superior outcome of adult T-cell leukemia/lymphoma under mogamulizumab treatment. 査読有り

    Sakamoto Y, Ishida T, Masaki A, Murase T, Yonekura K, Tashiro Y, Tokunaga M, Utsunomiya A, Ito A, Kusumoto S, Iida S, Ueda R, Inagaki H

    Blood   132 巻 ( 7 ) 頁: 758 - 761   2018年8月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blood  

    DOI: 10.1182/blood-2018-02-835991

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  5. Cyclin-dependent kinase 9 is a novel specific molecular target in adult T-cell leukemia/lymphoma. 査読有り

    Narita T, Ishida T, Ito A, Masaki A, Kinoshita S, Suzuki S, Takino H, Yoshida T, Ri M, Kusumoto S, Komatsu H, Imada K, Tanaka Y, Takaori-Kondo A, Inagaki H, Scholz A, Lienau P, Kuroda T, Ueda R, Iida S

    Blood   130 巻 ( 9 ) 頁: 1114 - 1124   2017年8月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blood  

    Cyclin-dependent kinase 9 (CDK9), a subunit of the positive transcription elongation factor b (P-TEFb) complex, regulates gene transcription elongation by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (RNAPII). The deregulation of CDK9/P-TEFb has important implications for many cancer types. BAY 1143572 is a novel and highly selective CDK9/P-TEFb inhibitor currently being investigated in phase 1 studies. We evaluated the therapeutic potential of BAY 1143572 in adult T-cell leukemia/lymphoma (ATL). As a result of CDK9 inhibition and subsequent inhibition of phosphorylation at serine 2 of the RNAPII CTD, BAY 1143572 decreased c-Myc and Mcl-1 levels in ATL-derived or human T-cell lymphotropic virus type-1 (HTLV-1)–transformed lines and primary ATL cells tested, leading to their growth inhibition and apoptosis. Median inhibitory concentrations for BAY 1143572 in ATL-derived or HTLV-1–transformed lines (n 5 8), primary ATL cells (n 5 11), and CD41 cells from healthy volunteers (n 5 5) were 0.535, 0.30, and 0.36 mM, respectively. Next, NOG mice were used as recipients of tumor cells from an ATL patient. BAY 1143572–treated ATL-bearing mice (once daily 12.5 mg/kg oral application) demonstrated significantly decreased ATL cell infiltration of the liver and bone marrow, as well as decreased human soluble interleukin-2 receptor levels in serum (reflecting the ATL tumor burden), compared with untreated mice (n 5 8 for both). BAY 1143572–treated ATL-bearing mice demonstrated significantly prolonged survival compared with untreated ATL-bearing mice (n 5 7 for both). Collectively, this study indicates that BAY 1143572 showed strong potential as a novel treatment of ATL.

    DOI: 10.1182/blood-2016-09-741983

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  6. Multicenter Phase II Study of Lenalidomide in Relapsed or Recurrent Adult T-Cell Leukemia/Lymphoma: ATLL-002. 査読有り

    Ishida T, Fujiwara H, Nosaka K, Taira N, Abe Y, Imaizumi Y, Moriuchi Y, Jo T, Ishizawa K, Tobinai K, Tsukasaki K, Ito S, Yoshimitsu M, Otsuka M, Ogura M, Midorikawa S, Ruiz W, Ohtsu T

    Journal of clinical oncology : official journal of the American Society of Clinical Oncology   34 巻 ( 34 ) 頁: 4086 - +   2016年12月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Clinical Oncology  

    Purpose: Few treatment options exist for adult T-cell leukemia/lymphoma (ATL), and the prognosis for this disease is poor. A phase I study of lenalidomide demonstrated preliminary antitumor activity in patients with relapsed ATL. The current phase II study evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed or recurrent ATL. Patients and Methods: Patients 20 years of age or older with acute, lymphoma, or unfavorable chronic subtype ATL, who had received one or more prior anti-ATL systemic chemotherapy and achieved stable disease or better on their last anti-ATL therapy with subsequent relapse or recurrence, were eligible. Patients received oral lenalidomide 25 mg/d continuously until disease progression or unacceptable toxicity. The primary end point was overall response rate; secondary end points included safety, tumor control rate (stable disease or better), time to response, duration of response, time to progression, progression-free survival, and overall survival. Results: Objective responses were noted in 11 of 26 patients (overall response rate, 42%; 95% CI, 23% to 63%), including four complete responses and one unconfirmed complete response. The tumor control rate was 73%. The median time to response and duration of response were 1.9 months and not estimable, respectively, and the median time to progression was 3.8 months. The median progression-free survival and overall survival were 3.8 and 20.3 months, respectively. The most frequent grade ≥ 3 adverse events were neutropenia (65%), leukopenia (38%), lymphopenia (38%), and thrombocytopenia (23%), which were all manageable and reversible. Conclusion: Lenalidomide demonstrated clinically meaningful antitumor activity and an acceptable toxicity profile in patients with relapsed or recurrent aggressive ATL, hinting at its potential to become a treatment option. Further investigations of lenalidomide in ATL and other mature T-cell neoplasms are warranted.

    DOI: 10.1200/JCO.2016.67.7732

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  7. Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study. 査読有り

    Ishida T, Jo T, Takemoto S, Suzushima H, Uozumi K, Yamamoto K, Uike N, Saburi Y, Nosaka K, Utsunomiya A, Tobinai K, Fujiwara H, Ishitsuka K, Yoshida S, Taira N, Moriuchi Y, Imada K, Miyamoto T, Akinaga S, Tomonaga M, Ueda R

    British journal of haematology   169 巻 ( 5 ) 頁: 672 - 682   2015年6月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:British Journal of Haematology  

    This multicentre, randomized, phase II study was conducted to examine whether the addition of mogamulizumab, a humanized anti-CC chemokine receptor 4 antibody, to mLSG15, a dose-intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T-cell leukaemia-lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15-plus-mogamulizumab arm (n = 29) were 52% [95% confidence interval (CI), 33-71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n = 24) were 33% (95% CI, 16-55%) and 75%, respectively. Grade ≥ 3 treatment-emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (≥10% difference) in the mLSG15-plus-mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15-plus-mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: NCT01173887.

    DOI: 10.1111/bjh.13338

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  8. Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma. 査読有り

    Ogura M, Ishida T, Hatake K, Taniwaki M, Ando K, Tobinai K, Fujimoto K, Yamamoto K, Miyamoto T, Uike N, Tanimoto M, Tsukasaki K, Ishizawa K, Suzumiya J, Inagaki H, Tamura K, Akinaga S, Tomonaga M, Ueda R

    Journal of clinical oncology : official journal of the American Society of Clinical Oncology   32 巻 ( 11 ) 頁: 1157 - +   2014年4月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Clinical Oncology  

    Purpose: CC chemokine receptor 4 (CCR4) is expressed by peripheral T-cell lymphomas (PTCLs) and is associated with poor outcomes. Mogamulizumab (KW-0761) is a defucosylated humanized anti-CCR4 antibody engineered to exert potent antibody-dependent cellular cytotoxicity. This multicenter phase II study evaluated the efficacy and safety of mogamulizumab in patients with relapsed PTCL and cutaneous T-cell lymphoma (CTCL). Patients and Methods: Mogamulizumab (1.0 mg/kg) was administered intravenously once per week for 8 weeks to patients with relapsed CCR4-positive PTCL or CTCL. The primary end point was the overall response rate, and the secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Results: A total of 38 patients were enrolled, and 37 patients received mogamulizumab. Objective responses were noted for 13 of 37 patients (35%; 95% CI, 20% to 53%), including five patients (14%) with complete response. The median PFS was 3.0 months (95% CI, 1.6 to 4.9 months), and the median OS was not calculated. The mean maximum and trough mogamulizumab concentrations (± standard deviation) after the eighth infusion were 45.9 ± 9.3 and 29.0 ± 13.3 μg/mL, respectively. The most common adverse events were hematologic events, pyrexia, and skin disorders, all of which were reversible and manageable. Conclusion: Mogamulizumab exhibited clinically meaningful antitumor activity in patients with relapsed PTCL and CTCL, with an acceptable toxicity profile. Further investigation of mogamulizumab for treatment of T-cell lymphoma is warranted. © 2014 by American Society of Clinical Oncology.

    DOI: 10.1200/JCO.2013.52.0924

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  9. HTLV-1 bZIP factor-specific CD4 T cell responses in adult T cell leukemia/lymphoma patients after allogeneic hematopoietic stem cell transplantation. 査読有り

    Narita T, Ishida T, Masaki A, Suzuki S, Ito A, Mori F, Yamada T, Ri M, Kusumoto S, Komatsu H, Miyazaki Y, Takatsuka Y, Utsunomiya A, Niimi A, Iida S, Ueda R

    Journal of immunology (Baltimore, Md. : 1950)   192 巻 ( 3 ) 頁: 940 - 947   2014年2月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Immunology  

    We document human T lymphotropic virus type 1 (HTLV-1) bZIP factor (HBZ)-specific CD4 T cell responses in an adult T cell leukemia/lymphoma (ATL) patient after allogeneic hematopoietic stem cell transplantation (HCT) and identified a novel HLADRB1 15:01-restricted HBZ-derived naturally presented minimum epitope sequence, RRRAEKKAADVA (HBZ114-125). This peptide was also presented on HLA-DRB1 15:02, recognized by CD4 T cells. Notably, HBZ-specific CD4 T cell responses were only observed in ATL patients after allogeneic HCT (4 of 9 patients) and not in nontransplanted ATL patients (0 of 10 patients) or in asymptomatic HTLV-1 carriers (0 of 10 carriers). In addition, in one acute-type patient, HBZ-specific CD4 T cell responses were absent in complete remission before HCT, but they became detectable after allogeneic HCT. We surmise that HTLV-1 transmission from mothers to infants through breast milk in early life induces tolerance to HBZ and results in insufficient HBZspecific T cell responses in HTLV-1 asymptomatic carriers or ATL patients. In contrast, after allogeneic HCT, the reconstituted immune system from donor-derived cells can recognize virus protein HBZ as foreign, and HBZ-specific immune responses are provoked that contribute to the graft-versus-HTLV-1 effect. Copyright © 2014 by The American Association of Immunologists, Inc.

    DOI: 10.4049/jimmunol.1301952

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  10. Stevens-Johnson Syndrome associated with mogamulizumab treatment of adult T-cell leukemia/lymphoma 招待有り 査読有り

    Ishida T., Ito A., Sato F., Kusumoto S., Iida S., Inagaki H., Morita A., Akinaga S., Ueda R.

    Cancer Science   104 巻 ( 5 ) 頁: 647 - 650   2013年5月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    We report an adult T-cell leukemia/lymphoma patient suffering from Stevens-Johnson Syndrome (SJS) during mogamulizumab (humanized anti-CCR4 monoclonal antibody) treatment. There was a durable significant reduction of the CD4+CD25highFOXP3+ regulatory T (Treg) cell subset in the patient's PBMC, and the affected inflamed skin almost completely lacked FOXP3-positive cells. This implies an association between reduction of the Treg subset by mogamulizimab and occurrence of SJS. The present case should contribute not only to our understanding of human pathology resulting from therapeutic depletion of Treg cells, but also alert us to the possibility of immune-related severe adverse events such as SJS when using mogamulizumab. We are currently conducting a clinical trial of mogamulizumab for CCR4-negative solid cancers (UMIN000010050), specifically aiming to deplete Treg cells. © 2013 Japanese Cancer Association.

    DOI: 10.1111/cas.12116

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  11. Defucosylated Anti-CCR4 Monoclonal Antibody (KW-0761) for Relapsed Adult T-Cell Leukemia-Lymphoma: A Multicenter Phase II Study 査読有り

    Takashi Ishida, Tatsuro Joh, Naokuni Uike, Kazuhito Yamamoto, Atae Utsunomiya, Shinichiro Yoshida, Yoshio Saburi, Toshihiro Miyamoto, Shigeki Takemoto, Hitoshi Suzushima, Kunihiro Tsukasaki, Kisato Nosaka, Hiroshi Fujiwara, Kenji Ishitsuka, Hiroshi Inagaki, Michinori Ogura, Shiro Akinaga, Masao Tomonaga, Kensei Tobinai, Ryuzo Ueda

    JOURNAL OF CLINICAL ONCOLOGY   30 巻 ( 8 ) 頁: 837 - 842   2012年3月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC CLINICAL ONCOLOGY  

    Purpose
    Adult T-cell leukemia-lymphoma (ATL) is usually resistant to conventional chemotherapies, and there are few other treatment options. Because CC chemokine receptor 4 (CCR4) is expressed on tumor cells from most patients with ATL, KW-0761, a humanized anti-CCR4 monoclonal antibody, which markedly enhances antibody-dependent cellular cytotoxicity, was evaluated in the treatment of patients with relapsed ATL.
    Patients and Methods
    A multicenter phase II study of KW-0761 for patients with relapsed, aggressive CCR4-positive ATL was conducted to evaluate efficacy, pharmacokinetic profile, and safety. The primary end point was overall response rate, and secondary end points included progression-free and overall survival from the first dose of KW-0761. Patients received intravenous infusions of KW-0761 once per week for 8 weeks at a dose of 1.0 mg/kg.
    Results
    Of 28 patients enrolled onto the study, 27 received at least one infusion of KW-0761. Objective responses were noted in 13 of 26 evaluable patients, including eight complete responses, with an overall response rate of 50% (95% CI, 30% to 70%). Median progression-free and overall survival were 5.2 and 13.7 months, respectively. The mean half-life period after the eighth infusion was 422 +/- 147 hours (+/- standard deviation). The most common adverse events were infusion reactions (89%) and skin rashes (63%), which were manageable and reversible in all cases.
    Conclusion
    KW-0761 demonstrated clinically meaningful antitumor activity in patients with relapsed ATL, with an acceptable toxicity profile. Further investigation of KW-0761 for treatment of ATL and other T-cell neoplasms is warranted. J Clin Oncol 30: 837-842. (C) 2012 by American Society of Clinical Oncology

    DOI: 10.1200/JCO.2011.37.3472

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  12. Defucosylated Humanized Anti-CCR4 Monoclonal Antibody KW-0761 as a Novel Immunotherapeutic Agent for Adult T-cell Leukemia/Lymphoma

    Toshihiko Ishii, Takashi Ishida, Atae Utsunomiya, Atsushi Inagaki, Hiroki Yano, Hirokazu Komatsu, Shinsuke Iida, Kazunori Imada, Takashi Uchiyama, Shiro Akinaga, Kenya Shitara, Ryuzo Ueda

    CLINICAL CANCER RESEARCH   16 巻 ( 5 ) 頁: 1520 - 1531   2010年3月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Purpose: Adult T-cell leukemia/lymphoma (ATLL) has a very poor prognosis. We have developed the humanized defucosylated anti-CC chemokine receptor 4 (CCR4) monoclonal antibody KW-0761 as a next generation immunotherapeutic agent. The first aim of the present study was to evaluate whether the antitumor activity of KW-0761 would likely be sufficient for therapeutic clinical application against ATLL. The second aim was to fully elucidate the mechanism of antibody-dependent cellular cytotoxicity (ADCC) mediated by this defucosylated monoclonal antibody.
    Experimental Design: The antitumor activity of KW-0761 against ATLL cell lines was evaluated in vitro using human cells and in mice in vivo. Primary ATLL cells from 23 patients were evaluated for susceptibility to autologous ADCC with KW-0761 by two independent methods.
    Results: KW-0761 showed potent antitumor activity against ATLL cell lines both in vitro and in the ATLL mouse model in vivo. In addition, KW-0761 showed potent antitumor activity mediated by highly enhanced ADCC against primary ATLL cells both in vitro and ex vivo in an autologous setting. The degree of KW-0761 ADCC against primary ATLL cells in an autologous setting was mainly determined by the amount of effector natural killer cells present, but not the amount of the target molecule CCR4 on the ATLL cell surface.
    Conclusion: KW-0761 should be sufficiently active for therapeutic clinical application for ATLL. In addition, combination treatment strategies that augment natural killer cell activity should be promising for amplifying the effect of KW-0761. In the near future, the actual efficacy of KW-0761 will be established in pivotal clinical trials. Clin Cancer Res; 16(5); 1520-31. (C)2010 AACR.

    DOI: 10.1158/1078-0432.CCR-09-2697

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    PubMed

  13. Regulatory T-cell function of adult T-cell leukemia/lymphoma cells 査読有り

    Hiroki Yano, Takashi Ishida, Atsushi Inagaki, Toshihiko Ishii, Shigeru Kusumoto, Hirokazu Komatsu, Shinsuke Iida, Atae Utsunomiya, Ryuzo Ueda

    INTERNATIONAL JOURNAL OF CANCER   120 巻 ( 9 ) 頁: 2052 - 2057   2007年5月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Adult T-cell leukemia/lymphoma (ATLL) patients are highly immunocompromised, but the underlying mechanism responsible for this state remains obscure. Recent studies demonstrated that FOXP3, which is a master control gene of naturally occurring regulatory T (Treg) cells, is expressed in the tumor cells from a subset of patients with ATLL. Since most ATLL cells express both CD4 and CD25, these tumors might originate from CD4(+)CD25(+)FOXP3(+) Treg cells, based on their phenotypic characteristics. However, whether ATLL cells actually function as Treg cells has not yet been clearly demonstrated. Here, we show that ATLL cells from a subset of patients are not only hypo-responsive to T-cell receptor-mediated activation, but also suppress the proliferation of autologous CD4(+) non-ATLL cells. Furthermore, ATLL cells from this subset of patients secrete only small amounts of IFN-gamma, and suppress IFN-gamma production by autologous CD4(+) non-ATLL cells. These are the first data showing that ATLL cells from a subset of patients function as Treg cells in an autologous setting. The present study provides novel insights into understanding the immunopathogenesis of ATLL, i.e., how HTLV-1-infected cells can survive in the face of host immune responses. It also adds to our understanding of ATLL patients' severely immunocompromised state. (c) 2007 Wiley-Liss, Inc.

    DOI: 10.1002/ijc.22536

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  14. Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege 査読有り

    T Ishida, T Ishii, A Inagaki, H Yano, H Komatsu, S Iida, H Inagaki, R Ueda

    CANCER RESEARCH   66 巻 ( 11 ) 頁: 5716 - 5722   2006年6月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Hodgkin lymphoma (HL) is characterized by the presence of a small number of tumor cells in a rich background of inflammatory cells, but the contribution of the abundant nontumor cells to HL pathogenesis is poorly understood. We showed that migratory CD4(+) cells induced by HL cells were hyporesponsive to T-cell receptor stimulation and suppressed the activation/proliferation of the effector CD4(+) T cells in an autologous setting. We further showed that HL cells in the affected lymph nodes were surrounded by a large number of lymphocytes expressing both CC chemokine receptor 4 (CCR4) and FOXP3. These findings indicate that the migratory cells induced by HL cells function as regulatory T (Treg) cells so that these cells create a favorable environment for the tumor cells to escape from host immune system. In addition, we showed that a chimeric anti-CCR4 monoclonal antibody (mAb) could deplete CCR4(+) T cells and inhibit the migration of CD4(+)CD25(+) T cells in vitro. Recognition of the importance of CCR4(+) Treg cells in the pathogenesis of HL will allow rational design of more effective treatments, such as use of an anti-CCR4 mAb, to overcome the suppressive effect of CCR4(+) Treg cells on the host immune response to tumor cells.

    DOI: 10.1158/0008-5472.CAN-06-0261

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  15. The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-cell leukemia/lymphoma 査読有り

    Takashi Ishida, Shinsuke Iida, Yoshiki Akatsuka, Toshihiko Ishii, Mikinori Miyazaki, Hirokazu Komatsu, Hiroshi Inagaki, Noriko Okada, Teizo Fujita, Kenya Shitara, Shiro Akinaga, Toshitada Takahashi, Atae Utsunomiya, Ryuzo Ueda

    Clinical Cancer Research   10 巻 ( 22 ) 頁: 7529 - 7539   2004年12月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell neoplasm with dismal prognosis, and no optimal therapy has been developed. We tested the defucosylated chimeric anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, KM2760, to develop a novel immunotherapy for this refractory tumor. In the presence of peripheral blood mononuclear cells (PBMCs) from healthy adult donors, KM2760 induced CCR4-specific antibody-dependent cellular cytotoxicity (ADCC) against CCR4-positive ATLL cell lines and primary tumor cells obtained from ATLL patients. We next examined the KM2760-induced ADCC against primary ATLL cells in an autologous setting. Antibody-dependent cellular cytotoxicity mediated by autologous effector cells was generally lower than that mediated by allogeneic control effector cells. However, a robust ADCC activity was induced in some cases, which was comparable with that mediated by allogeneic effector cells. It suggests that the ATLL patients' PBMCs retain substantial ADCC-effector function, although the optimal conditions for maximal effect have not yet been determined. In addition, we also found a high expression of FoxP3 mRNA and protein, a hallmark of regulatory T cells, in ATLL cells, indicating the possibility that ATLL cells originated from regulatory T cells. KM2760 reduced FoxP3 mRNA expression in normal PBMCs along with CCR4 mRNA by lysis of CCM4+ T cells in vitro. Our data suggest not only that the CCR4 molecule could be a suitable target for the novel antibody-based therapy for patients with ATLL but also that KM2760 may induce effective tumor immunity by reducing the number of regulatory T cells.

    DOI: 10.1158/1078-0432.CCR-04-0983

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  16. CXC chemokine receptor 3 and CC chemokine receptor 4 expression in T-cell and NK-cell lymphomas with special reference to clinicopathological significance for peripheral T-cell lymphoma, unspecified 査読有り

    T Ishida, H Inagaki, A Utsunomiya, Y Takatsuka, H Komatsu, S Iida, G Takeuchi, T Eimoto, S Nakamura, R Ueda

    CLINICAL CANCER RESEARCH   10 巻 ( 16 ) 頁: 5494 - 5500   2004年8月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    We recently reported expression of the chemokine receptors CXC chemokine receptor 3 (CXCR3) and CC chemokine receptor 4 (CCR4) in adult T-cell leukemia/ lymphoma and showed a preferential expression of CCR4 and its association with an unfavorable outcome. In the present study, we extend our adult T-cell leukemia/lymphoma study to other subtypes of T- and NK-cell lymphoma, to clarify whether a characteristic chemokine receptor expression pattern is obtained for each of the subtypes defined by the WHO classification. CXCR3 and CCR4 were rarely expressed in three well-defined subtypes, precursor T-lymphoblastic lymphoma, anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, and extranodal NK/T -cell lymphoma. A CXCR3-dominant expression pattern was observed in angioimmunoblastic T-cell lymphoma, while a CCR4-dominant expression pattern was observed in mycosis fungoides in transformation and in anaplastic lymphoma kinase-negative anaplastic large cell lymphoma. CXCR3 and CCR4 were heterogeneously expressed in peripheral T-cell lymphomas, unspecified (PTCLU). We next focused on PTCLU and analyzed the clinical significance of the chemokine receptors and their association with FoxP3, a hallmark of immunoregulatory T (Treg) cells. Multivariate analysis showed that CCR4 expression was an independent and significant unfavorable prognostic factor (P < 0.001). A significant correlation was found between mRNA expression of CCR4 and FoxP3, suggesting a possible association of CCR4-positive tumors with Treg cells and thereby with an immunocompromised state. Chemokine receptors may be useful not only for further characterization of the T- and NK-cell lymphomas but also in predicting clinical outcomes for patients. We suggest that a specific therapy targeting the CCR4 molecule may be developed as an alternative treatment for patients with CCR4-positive tumors.

    DOI: 10.1158/1078-0432.CCR-04-0371

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  17. Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: Its close association with skin involvement and unfavorable outcome

    T Ishida, A Utsunomiya, S Iida, H Inagaki, Y Takatsuka, S Kusumoto, G Takeuchi, S Shimizu, M Ito, H Komatsu, A Wakita, T Eimoto, K Matsushima, R Ueda

    CLINICAL CANCER RESEARCH   9 巻 ( 10 ) 頁: 3625 - 3634   2003年9月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Adult T-cell leukemia/lymphoma (ATLL) is a distinct clinical entity among mature T-cell neoplasms, and its causative agent has been confirmed to be long-term infection by human T-lymphotropic virus type 1. A recent study demonstrated frequent expression of a chemokine receptor, CC chemokine receptor (CCR)4, which is known as a Th2 marker but not CXC chemokine receptor (CXCR)3, which is known as a Th1 marker, among both ATLL- and human T-lymphotropic virus type 1-immortalized T cells. In this study, immunostaining analysis for CCR4 and CXCR3 expression in ATLL cells obtained from 103 patients with ATLL was performed, and the clinical parameters and overall survival of the CCR4-positive and -negative cases were compared. Ninety-one (88.3%) of the 103 cases were positive for CCR4 staining, whereas only 5 (4.9%) were positive for CXCR3 staining. Positivity for CCR4 was significantly associated with skin involvement (P < 0.05), although there were no significant differences in clinical characteristics between the CCR4-positive and -negative cases at the time of initial diagnosis. CCR4(+) ATLL cells may accumulate in the skin because of the expression of a CCR4 ligand, thymus and activation-regulated chemokine (TARC), on normal and inflamed cutaneous endothelia. As for survival analysis, positivity for CCR4 expression was extracted as an unfavorable prognostic factor as well as other factors, including the presence of B symptoms and extranodal involvement of more than one site. Multivariate analysis confirmed that CCR4 expression was an independent and significant prognostic factor (P < 0.05). Thus, our finding may provide a novel insight into not only the biological but also the clinical features of ATLL.

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  18. CCR7 alterations associated with inferior outcome of adult T-cell leukemia/lymphoma under mogamulizumab treatment 査読有り

    Sakamoto Yuma, Ishida Takashi, Masaki Ayako, Murase Takayuki, Ohtsuka Eiichi, Takeshita Morishige, Muto Reiji, Iwasaki Hiromi, Ito Asahi, Kusumoto Shigeru, Nakano Nobuaki, Tokunaga Masahito, Yonekura Kentaro, Tashiro Yukie, Iida Shinsuke, Utsunomiya Atae, Ueda Ryuzo, Inagaki Hiroshi

    HEMATOLOGICAL ONCOLOGY     2022年8月

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    担当区分:責任著者   記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Hematological Oncology  

    Adult T-cell leukemia/lymphoma (ATL) patients have a very poor prognosis. The humanized anti-CCR4 therapeutic monoclonal antibody, mogamulizumab, is a key agent for ATL treatment. Our previous integrated molecular analysis demonstrated that among all the driver genes in ATL, CCR7 gene alterations were significantly associated with clinical response to mogamulizumab. Accordingly, here we investigated the detailed clinical impact of CCR7 alterations in a larger cohort of ATL patients. These CCR7 alterations, most of which lead to C-terminus truncations, were observed in 27 of 223 patients (12%). For patients receiving mogamulizumab but not allogeneic hematopoietic stem cell transplantation (HSCT), CCR7 alterations were significantly associated with worse survival (median survival from the first dose of mogamulizumab of 0.7 years for 12 patients with CCR7 alterations vs. 1.6 years for 72 patients without, p = 0.020). On the other hand, the presence or absence of CCR7 alterations had no significant impact on survival in the entire cohort (median overall survival of 1.4 and 1.8 years, respectively, p = 0.901), or on the survival of patients receiving allogeneic HSCT (median survival from the day of transplantation of 0.9 years for 6 patients with CCR7 alterations and 1.4 years for 48 without, p = 0.543). Multivariate analysis indicated that patients with CCR4 alterations but lacking CCR7 alterations (n = 20) had significantly better survival after receiving mogamulizumab-containing treatments (hazard ratio for survival, 0.437, 95% confidence interval, 0.192–0.994). This study contributes to the establishment of precision medicine for ATL.

    DOI: 10.1002/hon.3072

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  19. Clinicopathological significance of CD28 overexpression in adult T-cell leukemia/lymphoma 国際誌

    Sakamoto Yuma, Ishida Takashi, Masaki Ayako, Takeshita Morishige, Iwasaki Hiromi, Yonekura Kentaro, Tashiro Yukie, Ito Asahi, Kusumoto Shigeru, Iida Shinsuke, Utsunomiya Atae, Ueda Ryuzo, Inagaki Hiroshi

    CANCER SCIENCE   113 巻 ( 1 ) 頁: 349 - 361   2022年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    CD28, one of the costimulatory molecules, has a pivotal role in T-cell activation, and its expression is strictly regulated in normal T cells. Gain-of-function genetic alterations involving CD28 have been frequently observed in adult T-cell leukemia/lymphoma (ATLL). These abnormalities, such as CD28 fusions and copy number variations, may not only confer continuous, prolonged, and enhanced CD28 signaling to downstream pathways but also induce overexpression of the CD28 protein. In this study, 120 ATLL cases were examined by immunohistochemistry for CD28 and its ligands CD80 and CD86, and their expression on tumor cells was semiquantitatively evaluated. CD28 was overexpressed in 55 (46%) cases, and CD80 or CD86 (CD80/CD86) was infrequently overexpressed in 12 (11%). Compared with non-overexpressers, CD28 overexpressers showed a higher frequency of CD28 genetic alterations and had an increased number of CD80/CD86-positive non-neoplastic cells infiltrating tumor microenvironment. In the entire ATLL patient cohort, CD28 overexpressers showed a significantly poorer overall survival (OS) compared with non-overexpressers (P =.001). The same was true for a subgroup who were treated with multidrug regimens with or without mogamulizumab. CD28 overexpression had no prognostic impact in the group who received allogeneic hematopoietic stem cell transplantation. In the multivariate analysis for OS, CD28 overexpression was selected as an independent risk factor. These results suggest ATLL patients with CD28 overexpression have more aggressive clinical course and are more refractory to treatment with multidrug chemotherapy. CD28 overexpression appears to be a novel unfavorable prognostic marker in ATLL patients, and further prospective studies are warranted to establish its prognostic significance.

    DOI: 10.1111/cas.15191

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.15191

  20. Clinical significance of the immunoglobulin G heavy-chain repertoire in peripheral blood mononuclear cells of adult T-cell leukaemia-lymphoma patients receiving mogamulizumab

    Nosaka Kisato, Kusumoto Shigeru, Nakano Nobuaki, Choi Ilseung, Yoshimitsu Makoto, Imaizumi Yoshitaka, Hidaka Michihiro, Sasaki Hidenori, Makiyama Junya, Ohtsuka Eiichi, Jo Tatsuro, Ogata Masao, Ito Asahi, Yonekura Kentaro, Tatetsu Hiro, Kato Takeharu, Kawakita Toshiro, Suehiro Youko, Ishitsuka Kenji, Iida Shinsuke, Matsutani Takaji, Utsunomiya Atae, Ueda Ryuzo, Ishida Takashi

    BRITISH JOURNAL OF HAEMATOLOGY     2021年10月

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    担当区分:責任著者   記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/bjh.17895

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/bjh.17895

  21. Clinical significance of TP53 mutations in adult T-cell leukemia/lymphoma

    Sakamoto Yuma, Ishida Takashi, Masaki Ayako, Murase Takayuki, Takeshita Morishige, Muto Reiji, Iwasaki Hiromi, Ito Asahi, Kusumoto Shigeru, Nakano Nobuaki, Tokunaga Masahito, Yonekura Kentaro, Tashiro Yukie, Iida Shinsuke, Utsunomiya Atae, Ueda Ryuzo, Inagaki Hiroshi

    BRITISH JOURNAL OF HAEMATOLOGY     2021年8月

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    担当区分:責任著者   記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:British Journal of Haematology  

    Adult T-cell leukaemia/lymphoma (ATL) patients have a poor prognosis. Here, we investigated the impact of TP53 gene mutations on prognosis of ATL treated in different ways. Among 177 patients, we identified 47 single nucleotide variants or insertion-deletions (SNVs/indels) of the TP53 gene in 37 individuals. TP53 copy number variations (CNVs) were observed in 38 patients. Altogether, 67 of 177 patients harboured TP53 SNVs/indels or TP53 CNVs, and were categorized as having TP53 mutations. In the entire cohort, median survival of patients with and without TP53 mutations was 1·0 and 6·7 years respectively (P < 0·001). After allogeneic haematopoietic stem cell transplantation (HSCT), median survival of patients with (n = 16) and without (n = 29) TP53 mutations was 0·4 years and not reached respectively (P = 0·001). For patients receiving mogamulizumab without allogeneic HSCT, the median survival from the first dose of antibody in patients with TP53 mutations (n = 27) was only 0·9 years, but 5·1 years in those without (n = 42; P < 0·001). Thus, TP53 mutations are associated with unfavourable prognosis of ATL, regardless of treatment strategy. The establishment of alternative modalities to overcome the adverse impact of TP53 mutations in patients with ATL is required.

    DOI: 10.1111/bjh.17749

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/bjh.17749

  22. Correction: GVHD-free, relapse-free survival provides novel clues for optimizing allogeneic-HSCT for adult T-cell leukemia/lymphoma (Bone Marrow Transplantation, (2021), 56, 1, (155-166), 10.1038/s41409-020-00996-y)

    Muranushi H., Shindo T., Hishizawa M., Tokunaga M., Wake A., Nakano N., Eto T., Hidaka M., Choi I., Miyamoto T., Uchida N., Moriuchi Y., Miyazaki Y., Fukuda T., Ichinohe T., Atsuta Y., Kato K., Yoshimitsu M., Ishida T., Utsunomiya A., Kato K., Suzumiya J., Tobai T., Nakase K., Nawa Y., Fukushima T., Asakura Y., Fujiwara H., Machida S., Sawayama Y., Inoue Y., Imada K., Yoshida I., Fuji S., Morishima S., Tomori S., Iemura T., Shimizu T., Morita-Fujita M., Kato K.

    Bone Marrow Transplantation   56 巻 ( 1 )   2021年1月

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    記述言語:日本語   出版者・発行元:Bone Marrow Transplantation  

    In the original version of this article, the legends to Figs. 1 and 2 were incorrect. This has now been corrected in the PDF and HTML versions of the article.

    DOI: 10.1038/s41409-020-01037-4

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  23. GVHD-free, relapse-free survival provides novel clues for optimizing allogeneic-HSCT for adult T-cell leukemia/lymphoma

    Muranushi H., Shindo T., Hishizawa M., Tokunaga M., Wake A., Nakano N., Eto T., Hidaka M., Choi I., Miyamoto T., Uchida N., Moriuchi Y., Miyazaki Y., Fukuda T., Ichinohe T., Atsuta Y., Yoshimitsu M., Ishida T., Utsunomiya A., Kato K., Suzumiya J., Tobai T., Nakase K., Nawa Y., Fukushima T., Choi I., Asakura Y., Fujiwara H., Machida S., Sawayama Y., Inoue Y., Imada K., Yoshida I., Fuji S., Fukuda T., Shindo T., Morishima S., Tomori S., Iemura T., Shimizu T., Morita-Fujita M., Kato K.

    Bone Marrow Transplantation   56 巻 ( 1 ) 頁: 155 - 166   2021年1月

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    記述言語:日本語   出版者・発行元:Bone Marrow Transplantation  

    The outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult T-cell leukemia/lymphoma (ATL) is still unsatisfactory. To illustrate the advantages and disadvantages of each donor source, we performed a nationwide retrospective study of graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) of patients with allo-HSCT-treated ATL. One-year GRFS did not significantly differ between patients who received related bone marrow transplantation (R-BMT; 26%, n = 117), related peripheral blood stem cell transplantation (R-PBSCT; 22%, n = 225), unrelated bone marrow transplantation (UR-BMT; 26%, n = 619), and cord blood transplantation (CBT; 21%, n = 359; p = 0.09). This was attributable to a low incidence of systemically-treated chronic GVHD after CBT (9% at 1 year) and reduced non-GVHD/relapse mortality after R-PBSCT (9% at 1 year). Among patients transplanted in complete remission (CR), 1-year overall survival after CBT (52%, n = 132) was not inferior to that after R-BMT (55%, n = 51), R-PBSCT (57%, n = 79), and UR-BMT (58%, n = 280; p = 0.15), and relapse rates were equivalent among the four sources (p = 0.19). Our results suggest that all donor sources are feasible for CR patients and that GRFS provides important clues toward optimizing allo-HSCT for ATL.

    DOI: 10.1038/s41409-020-00996-y

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  24. Clinical significance of CD28 gene-related activating alterations in adult T-cell leukaemia/lymphoma 査読有り

    Sakamoto Yuma, Ishida Takashi, Masaki Ayako, Takeshita Morishige, Iwasaki Hiromi, Yonekura Kentaro, Tashiro Yukie, Ito Asahi, Kusumoto Shigeru, Utsunomiya Atae, Iida Shinsuke, Ueda Ryuzo, Inagaki Hiroshi

    BRITISH JOURNAL OF HAEMATOLOGY   192 巻 ( 2 ) 頁: 281 - 291   2020年11月

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    担当区分:責任著者   記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:British Journal of Haematology  

    Multiple oncogenic events are involved in the development of adult T-cell leukaemia/lymphoma (ATL). Because CD28 plays a pivotal role in T-cell activation, we focused on alterations of the CD28 gene in ATL. We found multiple genetic abnormalities related to CD28 among the 144 patients enrolled in the present study. These involved gene fusions with the cytotoxic T-lymphocyte-associated antigen 4 or the inducible T-cell co-stimulator in 14 patients (10%), CD28-activating mutations in 3 (2%), and CD28 copy number variations in 34 (24%). Patients with such CD28 gene alterations were significantly younger than those without. In patients not receiving allogeneic haematopoietic stem cell transplantation, those with CD28 gene alterations tended to have a worse prognosis than those without. Finally, patients with chronic or smouldering ATL subtypes with CD28 gene alterations had a significantly worse prognosis than those without. These findings indicate that ATL, especially chronic or smouldering subtypes, have a more aggressive clinical course and are more refractory to conventional chemotherapies or mogamulizumab if they harbour CD28 gene alterations, likely because of continuous, prolonged, and enhanced CD28 activatory signalling. Novel treatment strategies to overcome the effects of these CD28 gene alterations are warranted.

    DOI: 10.1111/bjh.17211

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/bjh.17211

  25. Prognosis of patients with adult T-cell leukemia/lymphoma in Japan: A nationwide hospital-based study 査読有り

    Imaizumi Yoshitaka, Iwanaga Masako, Nosaka Kisato, Ishitsuka Kenji, Ishizawa Kenichi, Ito Shigeki, Amano Masahiro, Ishida Takashi, Uike Naokuni, Utsunomiya Atae, Ohshima Koichi, Tanaka Junji, Tokura Yoshiki, Tobinai Kensei, Watanabe Toshiki, Uchimaru Kaoru, Tsukasaki Kunihiro

    CANCER SCIENCE   111 巻 ( 12 ) 頁: 4567 - 4580   2020年10月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    Adult T-cell leukemia/lymphoma (ATL) is a mature T-cell neoplasm and is classified into four subtypes (acute, lymphoma, chronic, and smoldering) according to the Shimoyama classification, established in 1991 through several nationwide surveys based on the clinical diversity of patients diagnosed in 1983-1987 in Japan. Thereafter, no such studies have been conducted. Recently, we conducted a nationwide hospital survey using the method of the 1980s studies, collected baseline data on 996 ATL patients diagnosed in 2010-2011 from 126 hospitals, and reported their unique epidemiological characteristics. Here, we report the follow-up results of registered ATL patients with the goal of evaluating current prognoses and treatment modalities as of 2016-2017. Of 770 evaluable patients, 391 (50.8%) had acute-type, 192 (24.9%) had lymphoma-type, 106 (13.8%) had chronic-type, and 81 (10.5%) had smoldering-type ATL. The initial therapy regimens used for acute/lymphoma-type ATL were vincristine, cyclophosphamide, doxorubicin and prednisone, followed by doxorubicin, ranimustine, and prednisone and then by vindesine, etoposide, carboplatin, and prednisone (VCAP-AMP-VECP)-like in 38.5/41.7% and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like in 14.6/13.7% of patients. Allogeneic hematopoietic stem cell transplantation was used to treat 15.9/10.4% of acute/lymphoma-type ATL patients. The 4-year survival rates (the median survival time, days) for acute-, lymphoma-, unfavorable chronic-, favorable chronic-, and smoldering-type ATL were 16.8% (252), 19.6% (305), 26.6% (572), 62.1% (1937), and 59.8% (1851), respectively. The 4-year survival rates for acute- and lymphoma-type ATL improved compared with those reported in 1991, but those for chronic- and smoldering-type ATL were not. Further efforts are warranted to develop more efficient therapeutic strategies to improve the prognosis of ATL in Japan.

    DOI: 10.1111/cas.14658

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.14658

  26. Immunohistochemistry for CCR4C-terminus predicts CCR4 mutations and mogamulizumab efficacy in adult T-cell leukemia/lymphoma 査読有り

    Fujii Keiichiro, Sakamoto Yuma, Masaki Ayako, Murase Takayuki, Tashiro Yukie, Yonekura Kentaro, Utsunomiya Atae, Ito Asahi, Kusumoto Shigeru, Iida Shinsuke, Ueda Ryuzo, Ishida Takashi, Inagaki Hiroshi

    JOURNAL OF PATHOLOGY CLINICAL RESEARCH   7 巻 ( 1 ) 頁: 52 - 60   2020年10月

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    担当区分:責任著者   記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Pathology: Clinical Research  

    Mogamulizumab targets extracellular N-terminal domain of CCR4, which is expressed in most adult T-cell leukemia/lymphoma (ATL) cases. Recently, we reported that CCR4 C-terminal gain-of-function mutations were frequent in ATL cases, and a subgroup with these mutations who were treated without allogenic hematopoietic stem cell transplantation (HSCT) and with mogamulizumab-containing [HSCT (−) and mogamulizumab (+)] regimens had a superior survival rate. Although these mutations are most likely a biomarker for predicting a strong response to mogamulizumab, their detection is time-consuming and costly. A more convenient screening tool may be necessary in the clinical setting. In this study, the clinicopathological importance of immunohistochemistry for the CCR4 N-terminus (CCR4-N-IHC) and C-terminus (CCR4-C-IHC) was examined in a large ATL cohort (n = 92). We found that CCR4-C-IHC, but not CCR4-N-IHC, was inversely correlated with the CCR4 mutation status. In ATL patients negative for CCR4-C-IHC, a subgroup treated with HSCT (−) and mogamulizumab (+) regimens showed a significantly better prognosis. In addition, CCR4-C-IHC was found to be a useful marker for high-sensitivity screening of the CCR4 mutational status (87%). The present study suggests that CCR4-C-IHC may be useful for identifying ATL patients harboring mutated CCR4 who may benefit from the superior efficacy of mogamulizumab-containing regimens and that CCR4-C-IHC may be a rapid and cost-efficient tool for screening for CCR4 mutation status.

    DOI: 10.1002/cjp2.180

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cjp2.180

  27. Clinical significance of tryptophan catabolism in follicular lymphoma 査読有り 国際誌

    Masaki Ayako, Ishida Takashi, Maeda Yasuhiro, Ito Asahi, Suzuki Susumu, Narita Tomoko, Kinoshita Shiori, Yoshida Takashi, Ri Masaki, Kusumoto Shigeru, Komatsu Hirokazu, Inagaki Hiroshi, Ueda Ryuzo, Choi Ilseung, Suehiro Youko, Iida Shinsuke

    HEMATOLOGICAL ONCOLOGY   38 巻 ( 5 ) 頁: 742 - 753   2020年9月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Hematological Oncology  

    The enzyme, indoleamine 2,3-dioxygenase 1 (IDO), catabolizes tryptophan (Trp) in the kynurenine (Kyn) pathway, and is important in suppressing antitumor immune responses in the tumor microenvironment. With regard to previously untreated patients with follicular lymphoma (FL), we sought to establish the prognostic significance of Trp catabolism in this disease. Serum Trp and Kyn levels in 110 patients with FL were quantified, and their relationship to different clinical parameters studied. IDO expression in the lymph nodes of affected patients was studied. Study participants included 54 males and 56 females (age range 39–86, median 62 years), showing a 5-year overall survival (OS) rate of 78.5%. Patients with a high Kyn level (5-year OS, 65.0% vs. 81.7%; p = 0.026), high Kyn/Trp ratio (71.1% vs. 81.7%; p = 0.002), and low hemoglobin (Hb) level (<12.0 g/dL; p = 0.001; a component of FL international prognostic indexes) demonstrated a significantly shorter OS. Multivariate analysis included the following 10 variables: age, sex, serum β2-microglobulin, Hb, longest diameter of the largest involved node, Ann Arbor stage, serum lactate dehydrogenase, histologic grading, B symptoms, and serum Kyn/Trp ratio; a lower Hb level and a high Kyn/Trp ratio (HR, 3.239; 95% CI, 1.296–8.096) led to a significantly inferior OS. In the microenvironment, some CD11c-positive myeloid dendritic cells but not FL tumor cells were found to produce IDO. Overall, measuring levels of serum Kyn and Trp in individual patients with FL contributed to predicting their prognosis.

    DOI: 10.1002/hon.2804

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  28. Autocrine HGF/c-Met signaling pathway confers aggressiveness in lymph node adult T-cell leukemia/lymphoma 査読有り

    Totani Haruhito, Shinjo Keiko, Suzuki Miho, Katsushima Keisuke, Mase Shoko, Masaki Ayako, Ito Asahi, Ri Masaki, Kusumoto Shigeru, Komatsu Hirokazu, Ishida Takashi, Inagaki Hiroshi, Iida Shinsuke, Kondo Yutaka

    ONCOGENE   39 巻 ( 35 ) 頁: 5782 - 5794   2020年8月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Oncogene  

    Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasm. While ATL cells in peripheral blood (PB-ATL) are sensitive to anti-CC chemokine receptor 4 treatment, non–PB-ATLs, including lymph node ATLs (LN-ATLs), are more aggressive and resistant. We examined characteristic cytokines and growth factors that allow non–PB-ATLs to proliferate and invade compared with PB-ATLs. Protein array analysis revealed hepatocyte growth factor (HGF) and C-C motif chemokine 2 (CCL2) were significantly upregulated in non–PB-ATLs compared with PB-ATLs. The HGF membrane receptor, c-Met, was expressed in PB-ATL and non–PB-ATL cell lines, but CCR2, a CCL2 receptor, was not. Immunohistochemical analysis in clinical ATLs revealed high HGF expression in LNs, pharynx, bone marrow, and tonsils. The HGF/c-Met signaling pathway was active downstream in non–PB-ATLs. Downregulation of HGF/c-Met by siRNA or chemical inhibitors decreased in vitro and in vivo proliferation and invasion by non–PB-ATLs. Treatment with bromodomain and extra-terminal motif inhibitor suppressed HGF expression and decreased levels of histone H3 lysine 27 acetylation (H3K27Ac) and bromodomain-containing protein 4 (BRD4) binding promoter and enhancer regions, suppressing non–PB-ATL cellular growth. Our data indicate H3K27Ac/BRD4 epigenetics regulates the HGF/c-MET pathway in ATLs; targeting this pathway may improve treatment of aggressive non–PB-ATLs.

    DOI: 10.1038/s41388-020-01393-x

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    その他リンク: http://www.nature.com/articles/s41388-020-01393-x

  29. Root-knot nematodes induce gall formation by recruiting developmental pathways of post-embryonic organogenesis and regeneration to promote transient pluripotency.

    Olmo R, Cabrera J, Díaz-Manzano FE, Ruiz-Ferrer V, Barcala M, Ishida T, García A, Andrés MF, Ruiz-Lara S, Verdugo I, Pernas M, Fukaki H, Del Pozo JC, Moreno-Risueno MÁ, Kyndt T, Gheysen G, Fenoll C, Sawa S, Escobar C

    The New phytologist   227 巻 ( 1 ) 頁: 200 - 215   2020年7月

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    記述言語:英語  

    DOI: 10.1111/nph.16521

    PubMed

  30. Prognostic significance of the radiologic features of pneumonitis induced by anti-PD-1 therapy.

    Watanabe S, Ota T, Hayashi M, Ishikawa H, Otsubo A, Shoji S, Nozaki K, Ichikawa K, Kondo R, Miyabayashi T, Miura S, Tanaka H, Abe T, Okajima M, Terada M, Ishida T, Iwashima A, Sato K, Yoshizawa H, Kikuchi T

    Cancer medicine   9 巻 ( 9 ) 頁: 3070 - 3077   2020年5月

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    記述言語:英語  

    DOI: 10.1002/cam4.2974

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  31. DESHIMA on ASTE: On-Sky Responsivity Calibration of the Integrated Superconducting Spectrometer

    Takekoshi Tatsuya, Karatsu Kenichi, Suzuki Junya, Tamura Yoichi, Oshima Tai, Taniguchi Akio, Asayama Shin'ichiro, Bakx Tom J. L. C., Baselmans Jochem J. A., Bosma Sjoerd, Bueno Juan, Chin Kah Wuy, Fujii Yasunori, Fujita Kazuyuki, Huiting Robert, Ikarashi Soh, Ishida Tsuyoshi, Ishii Shun, Kawabe Ryohei, Klapwijk Teun M., Kohno Kotaro, Kouchi Akira, Llombart Nuria, Maekawa Jun, Murugesan Vignesh, Nakatsubo Shunichi, Naruse Masato, Ohtawara Kazushige, Pascual Laguna Alejandro, Suzuki Koyo, Thoen David J., Tsukagoshi Takashi, Ueda Tetsutaro, de Visser Pieter J., van der Werf Paul P., Yates Stephen J. C., Yoshimura Yuki, Yurduseven Ozan, Endo Akira

    JOURNAL OF LOW TEMPERATURE PHYSICS   199 巻 ( 1-2 ) 頁: 231 - 239   2020年4月

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    記述言語:日本語   出版者・発行元:Journal of Low Temperature Physics  

    We are developing an ultra-wideband spectroscopic instrument, DESHIMA (DEep Spectroscopic HIgh-redshift MApper), based on the technologies of an on-chip filter bank and microwave kinetic inductance detector (MKID) to investigate dusty starburst galaxies in the distant universe at millimeter and submillimeter wavelengths. An on-site experiment of DESHIMA was performed using the ASTE 10-m telescope. We established a responsivity model that converts frequency responses of the MKIDs to line-of-sight brightness temperature. We estimated two parameters of the responsivity model using a set of skydip data taken under various precipitable water vapor (PWV 0.4–3.0 mm) conditions for each MKID. The line-of-sight brightness temperature of sky is estimated using an atmospheric transmission model and the PWVs. As a result, we obtain an average temperature calibration uncertainty of 1 σ= 4 %, which is smaller than other photometric biases. In addition, the average forward efficiency of 0.88 in our responsivity model is consistent with the value expected from the geometrical support structure of the telescope. We also estimate line-of-sight PWVs of each skydip observation using the frequency response of MKIDs and confirm the consistency with PWVs reported by the Atacama Large Millimeter/submillimeter Array.

    DOI: 10.1007/s10909-020-02338-0

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  32. Feed-forward regulatory loop driven by IRF4 and NF-kappa B in adult T-cell leukemia/lymphoma 査読有り 国際誌

    Wong Regina Wan Ju, Tan Tze King, Amanda Stella, Phuong Cao Thi Ngoc, Leong Wei Zhong, Tan Shi Hao, Asamitsu Kaori, Hibi Yurina, Ueda Ryuzo, Okamoto Takashi, Ishida Takashi, Iida Shinsuke, Sanda Takaomi

    BLOOD   135 巻 ( 12 ) 頁: 934 - 947   2020年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blood  

    Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive hematological malignancy derived from mature CD4+ T-lymphocytes. Here, we demonstrate the transcriptional regulatory network driven by 2 oncogenic transcription factors, IRF4 and NF-κB, in ATL cells. Gene expression profiling of primary ATL samples demonstrated that the IRF4 gene was more highly expressed in ATL cells than in normal T cells. Chromatin immunoprecipitation sequencing analysis revealed that IRF4-bound regions were more frequently found in super-enhancers than in typical enhancers. NF-κB was found to co-occupy IRF4-bound regulatory elements and formed a coherent feed-forward loop to coordinately regulate genes involved in T-cell functions and development. Importantly, IRF4 and NF-κB regulated several cancer genes associated with super-enhancers in ATL cells, including MYC, CCR4, and BIRC3. Genetic inhibition of BIRC3 induced growth inhibition in ATL cells, implicating its role as a critical effector molecule downstream of the IRF4-NF-κB transcriptional network.

    DOI: 10.1182/blood.2019002639

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  33. Final results of a phase I study of carfilzomib, lenalidomide, and dexamethasone for heavily pretreated multiple myeloma

    Sugiura I.

    International Journal of Hematology   111 巻 ( 1 ) 頁: 57-64   2020年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/s12185-019-02754-3

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  34. CCR4 is rarely expressed in CCR4-mutated T/NK-cell lymphomas other than adult T-cell leukemia/lymphoma. 査読有り

    Sakamoto Y, Fujii K, Murase S, Nakano S, Masaki A, Murase T, Kusumoto S, Iida S, Utsunomiya A, Ueda R, Ishida T, Inagaki H

    International journal of hematology   110 巻 ( 4 ) 頁: 389 - 392   2019年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Hematology  

    CCR4 is expressed on tumor cells of most patients with adult T-cell leukemia/lymphoma (ATL). Gain-of-function mutations of the CCR4 gene in ATL patients may be associated with alterations at the carboxyl terminus, a finding which led to a high efficacy anti-CCR4 antibody, mogamulizumab. Only a few studies have reported CCR4 protein expression and genomic CCR4 mutations in non-ATL T/NK-cell lymphomas. Furthermore, an association between CCR4 protein expression, genomic CCR4 mutations, and transcript CCR4 mutations has not been well analyzed. The T/NK-cell lymphomas (n = 226) enrolled in this study were examined for CCR4 expression by immunohistochemistry. CCR4 mutations in the codons 322–348 were detected by direct sequencing and a SNaPshot Multiplex assay. CCR4 protein expression was positive in 48/52 (92%) and 58/174 (33%) of ATL and non-ATL cases, respectively, and genomic CCR4 mutations were detected in 17/52 (33%) and 6/174 (3.4%), respectively. While all 17 ATL cases with genomic CCR4 mutations were positive for CCR4 protein expression, five of six mutated non-ATL cases were negative for CCR4 protein expression and transcript CCR4 mutations. This study suggests that frequencies of CCR4 expression and genomic CCR4 mutations and an association between the two may be considerably different between ATL cases and non-ATL T/NK-cell lymphomas.

    DOI: 10.1007/s12185-019-02728-5

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  35. Carfilzomib monotherapy in Japanese patients with relapsed or refractory multiple myeloma: A phase 1/2 study

    Iida S.

    Cancer Science   110 巻 ( 9 ) 頁: 2924-2932   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/cas.14139

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  36. Exophiala dermatitidis Fungemia Diagnosed Using Time-of-flight Mass Spectrometry during Chemotherapy for Malignant Lymphoma and Successful Treatment with Voriconazole. 査読有り

    Yoshida T, Tachita T, Fujinami H, Oshima Y, Sasaki H, Marumo Y, Narita T, Ito A, Ri M, Kusumoto S, Ishida T, Komatsu H, Iida S

    Internal medicine (Tokyo, Japan)   58 巻 ( 15 ) 頁: 2219 - 2224   2019年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Internal Medicine  

    Infectious diseases, including those caused by fungi, remain important issues in patients receiving malignant lymphoma chemotherapy. We herein report a rare case of Exophiala dermatitidis fungemia during chemotherapy in a 67-year-old woman admitted to our hospital. She had a fever that could not be resolved despite antifungal therapy. Yeast-like fungi were detected in blood culture samples, but biochemical identification was difficult. E. dermatitidis, a black mold, was identified using time-of-flight mass spectrometry. The patient finally improved after her treatment was switched to voriconazole. Fungal infection is difficult to diagnose and treat, but this novel approach can improve patients’ outcomes.

    DOI: 10.2169/internalmedicine.2082-18

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  37. A retrospective analysis of haplo-identical HLA-mismatch hematopoietic transplantation without posttransplantation cyclophosphamide for GVHD prophylaxis in patients with adult T-cell leukemia-lymphoma

    Yoshimitsu Makoto, Utsunomiya Atae, Fuji Shigeo, Fujiwara Hiroshi, Fukuda Takahiro, Ogawa Hiroyasu, Takatsuka Yoshifusa, Ishitsuka Kenji, Yokota Akira, Okumura Hirokazu, Ishii Kazuyoshi, Nishikawa Akinori, Eto Tetsuya, Yonezawa Akihito, Miyashita Kaname, Tsukada Junichi, Tanaka Junji, Atsuta Yoshiko, Kato Koji, Ishida Takashi, Utsunomiya Atae, Suzumiya Junji, Takatsuka Yoshifusa, Tobai Tomomi, Nakase Koichi, Nawa Yuichiro, Hishizawa Masakatsu, Fukushima Takuya, Masuda Masato, Wake Atsushi, Ilseung Choi, Asakura Yoshitaka, Nakano Nobuaki, Fujiwara Hiroshi, Machida Shinichiro, Sawayama Yasushi, Tada Kohei, Inoue Yoshitaka, Imada Kazunori, Yoshida Isao, Yoshimitsu Makoto, Fuji Shigeo, Fukuda Takahiro, Shindo Takero, Tokunaga Masahito, Muranushi Hiroyuki, Morishima Satoko, Tomori Shohei, Iemura Tomoki

    BONE MARROW TRANSPLANTATION   54 巻 ( 8 ) 頁: 1266 - 1274   2019年8月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/s41409-018-0400-5

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  38. Impact of chromosomal abnormalities on the efficacy of lenalidomide plus dexamethasone treatment in patients with relapsed/refractory multiple myeloma. 査読有り

    Yoshida T, Ri M, Fujinami H, Oshima Y, Tachita T, Marumo Y, Sasaki H, Kinoshita S, Totani H, Narita T, Masaki A, Ito A, Kusumoto S, Ishida T, Komatsu H, Iida S

    International journal of hematology   110 巻 ( 2 ) 頁: 228 - 236   2019年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Hematology  

    Lenalidomide is an effective therapeutic agent for multiple myeloma (MM). However, its efficacy in the context of chromosomal abnormalities (CA) is poorly understood. We retrospectively analyzed 83 patients with relapsed/refractory (RR) MM, who received lenalidomide plus low-dose dexamethasone (Ld), in the context of CA. The median age and number of prior therapies were 69 and 2, respectively. Three, 11, 45, and 19 patients achieved complete response, very good partial response, partial response, and stable disease, respectively. Median progression-free survival (PFS) and overall survival (OS) were 11.1 and 38.8 months, respectively. Seventy-two patients were evaluated for frequently observed translocations; median PFS was 24.4 months in 20 patients with t(11;14), 13.0 months in 16 patients with t(4;14), and 3.7 months in seven patients with t(14;16). G-banded karyotype analysis detected 11 hypodiploid patients, who had shorter PFS and OS (2.5 and 6.2 months, respectively) compared to others (13.0 and 43.7 months, respectively). Hypodiploid patients showed poor clinical outcome, whereas patients with t(11;14) showed favorable outcome. In summary, the present study presents the clinical impact of chromosomal abnormalities on the outcome of Ld therapy, and contributes to understanding the appropriate choice of lenalidomide-based therapy to achieve effective treatment of RR MM.

    DOI: 10.1007/s12185-019-02669-z

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  39. Pre- and post-transplant ponatinib for a patient with acute megakaryoblastic blast phase chronic myeloid leukemia with T315I mutation who underwent allogeneic hematopoietic stem cell transplantation. 査読有り

    Sasaki H, Mitani S, Kusumoto S, Marumo Y, Asano A, Yoshida T, Narita T, Ito A, Yano H, Ri M, Ishida T, Komatsu H, Iida S

    International journal of hematology   110 巻 ( 1 ) 頁: 119 - 123   2019年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Hematology  

    A 42-year-old female complaining of fever and night sweats was diagnosed with acute megakaryoblastic blast phase chronic myeloid leukemia (CML-BP). She had massive splenomegaly, left pleural effusion with leukemia infiltration, and moderate myelofibrosis. She received dasatinib monotherapy (140 mg/day) as for induction, after which her pleural effusion rapidly resolved and hematological remission was achieved. However, CML relapsed 4 months after starting dasatinib due to increased BCR-ABL fusion signals in the peripheral blood. The T315I mutation was also detected at the recurrence of CML. As a salvage treatment, ponatinib monotherapy (45 mg/day) was started immediately. After 5 months, BCR-ABL fusion signals decreased to 5%, and myelofibrosis improved from MF Grade 2 to 1; she then underwent allogeneic bone marrow transplantation from an unrelated donor. However, the graft failed, and cord blood transplantation (CBT) was performed. Ponatinib (15 mg/day) was continued after CBT as a maintenance treatment, with molecular complete response continuing for more than 1 year with no severe adverse events, including cardiovascular events. There is limited evidence regarding the optimal dose and schedule of ponatinib before and after allogeneic hematopoietic stem cell transplantation, especially in patients with CML-BP having T315I mutation; thus, well-designed clinical trials are warranted.

    DOI: 10.1007/s12185-019-02628-8

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  40. 成人T細胞性白血病/リンパ腫におけるCD28遺伝子異常の臨床病理学的意義

    坂本 祐真, 正木 彩子, 村瀬 貴幸, 藤井 慶一郎, 上田 佳緒璃, 伊藤 旭, 石田 高司, 稲垣 宏

    日本病理学会会誌   108 巻 ( 1 ) 頁: 284 - 284   2019年4月

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    記述言語:日本語   出版者・発行元:(一社)日本病理学会  

  41. Revised Adult T-Cell Leukemia-Lymphoma International Consensus Meeting Report. 査読有り

    Cook LB, Fuji S, Hermine O, Bazarbachi A, Ramos JC, Ratner L, Horwitz S, Fields P, Tanase A, Bumbea H, Cwynarski K, Taylor G, Waldmann TA, Bittencourt A, Marcais A, Suarez F, Sibon D, Phillips A, Lunning M, Farid R, Imaizumi Y, Choi I, Ishida T, Ishitsuka K, Fukushima T, Uchimaru K, Takaori-Kondo A, Tokura Y, Utsunomiya A, Matsuoka M, Tsukasaki K, Watanabe T

    Journal of clinical oncology : official journal of the American Society of Clinical Oncology   37 巻 ( 8 ) 頁: 677 - 687   2019年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1200/JCO.18.00501

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  42. Follow-up of a randomised phase II study of chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: impact on allogeneic haematopoietic stem cell transplantation. 査読有り 国際誌

    Ishida T, Jo T, Takemoto S, Suzushima H, Suehiro Y, Choi I, Yoshimitsu M, Saburi Y, Nosaka K, Utsunomiya A, Kobayashi Y, Yamamoto K, Fujiwara H, Ishitsuka K, Yoshida S, Taira N, Imada K, Kato K, Moriuchi Y, Yoshimura K, Takahashi T, Tobinai K, Ueda R

    British journal of haematology   184 巻 ( 3 ) 頁: 479 - 483   2019年2月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:British Journal of Haematology  

    DOI: 10.1111/bjh.15123

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  43. Quantitatively immunological characterization of mogamulizumab skin disorders in ATL patients 査読有り

    Asahi Ito, Yui Suzuki, Ayako Masaki, Shinichiro Yoshida, Hitoshi Suzushima, Shigeki Takemoto, Atae Utsunomiya, Toshihiko Ishii, Masanori Hiura, Takeshi Takahashi, Satoshi Yurimoto, Hiroshi Inagaki, Akimichi Morita, Shinsuke Iida, Takashi Ishida

    J Cutan Immunol Allergy.   ( 2 ) 頁: 102 - 107   2019年

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    担当区分:最終著者  

    DOI: 10.1002/cia2.12070

  44. Cyclin-dependent kinase 9 as a potential specific molecular target in NK-cell leukemia/lymphoma. 査読有り

    Kinoshita S, Ishida T, Ito A, Narita T, Masaki A, Suzuki S, Yoshida T, Ri M, Kusumoto S, Komatsu H, Shimizu N, Inagaki H, Kuroda T, Scholz A, Ueda R, Sanda T, Iida S

    Haematologica   103 巻 ( 12 ) 頁: 2059 - 2068   2018年12月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Haematologica  

    BAY 1143572 is a highly selective inhibitor of cyclin-dependent kinase 9/positive transcription elongation factor b. It has entered phase I clinical studies. Here, we have assessed the utility of BAY 1143572 for treating natural killer (NK) cell leukemias/lymphomas that have a poor prognosis, namely extranodal NK/T-cell lymphoma, nasal type and aggressive NK-cell leukemia, in a preclinical mouse model in vivo as well as in tissue culture models in vitro. Seven NK-cell leukemia/lymphoma lines and primary aggressive NK-cell leukemia cells from two individual patients were treated with BAY 1143572 in vitro. Primary tumor cells from an aggressive NK-cell leukemia patient were used to establish a xenogeneic murine model for testing BAY 1143572 therapy. Cyclin-dependent kinase 9 inhibition by BAY 1143572 resulted in prevention of phosphorylation at the serine 2 site of the C-terminal domain of RNA polymerase II. This resulted in lower c-Myc and Mcl-1 levels in the cell lines, causing growth inhibition and apoptosis. In aggressive NK-cell leukemia primary tumor cells, exposure to BAY 1143572 in vitro resulted in decreased Mcl-1 protein levels resulting from inhibition of RNA polymerase II C-terminal domain phosphorylation at the serine 2 site. Orally administering BAY 1143572 once per day to aggressive NK-cell leukemia-bearing mice resulted in lower tumor cell infiltration into the bone marrow, liver, and spleen, with less export to the periphery relative to control mice. The treated mice also had a survival advantage over the untreated controls. The specific small molecule targeting agent BAY1143572 has potenti al for treating NK-cell leukemia/lymphoma.

    DOI: 10.3324/haematol.2018.191395

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  45. Unsuppressed serum albumin levels may jeopardize the clinical relevance of the international staging system to patients with light chain myeloma

    Kasamatsu T., Ozaki S., Saitoh T., Konishi J., Sunami K., Itagaki M., Asaoku H., Cho T., Handa H., Hagiwara S., Wakayama T., Negoro A., Takezako N., Harada N., Kuroda Y., Nakaseko C., Miyake T., Inoue N., Hata H., Shimazaki C., Ohno T., Kuroda J., Murayama T., Kobayashi T., Abe M., Ishida T., Nagura E., Shimizu K.

    Hematological Oncology   36 巻 ( 5 ) 頁: 792 - 800   2018年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Hematological Oncology  

    The international staging system (ISS) is the most commonly used risk-stratification system for patients with multiple myeloma (MM) and is determined by serum albumin and β2-microglobulin levels. In the two determinants, β2-microglobulin levels are frequently observed to be elevated in patients with myeloma, particularly in those with renal impairment. In comparison with patients with intact immunoglobulin myeloma, patients with LC myeloma do not necessarily show decreased levels of serum albumin. The clinical impact of ISS in patients with LCMM, in particular the distinction between ISS I and II, may be complicated due to non-decreased levels of serum albumin in both stages. Accordingly, we have attempted to assess clinical relevance of the ISS in patients with LC myeloma. The clinical data of 1899 patients with MM diagnosed between January 2001 and December 2012 were collected from 38 affiliated hospitals of the Japanese Society of Myeloma. Significant difference was not found between stage I (n = 72) and stage II (n = 92) in LC myeloma patients (n = 307). The mean serum albumin concentration of patients with LC myeloma was within the reference range but higher than that of patients with IgG + IgA myeloma (n = 1501), which complicates the distinction between ISS stage I and II myeloma. Patients with LC myeloma had low frequencies of t(4; 14) and high frequency of elevated lactate dehydrogenase, and despite a relevant amount of missing data in our registry (R-ISS stage I; n = 11, stage II; n = 32, and stage III: n = 18), the information included in the R-ISS scoring system seems to be more accurate than ISS to obtain a reliable risk stratification approach in non-ISS stage III LC myeloma patients.

    DOI: 10.1002/hon.2559

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  46. The roles of HGF/c-Met pathway in adult T-cell leukemia/lymphoma

    Totani Haruhito, Shinjo Keiko, Tasaki Yoshihiko, Murashima Akihiro, Mase Shoko, Yamamichi Akane, Suzuki Miho, Katsushima Keisuke, Ishida Takashi, Iida Shinsuke, Kondo Yutaka

    CANCER SCIENCE   109 巻   頁: 508-508   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Web of Science

  47. 成人T細胞白血病/リンパ腫におけるHGF/c-Met経路の役割(The roles of HGF/c-Met pathway in adult T-cell leukemia/lymphoma)

    戸谷 治仁, 新城 恵子, 田崎 慶彦, 村嶋 明大, 間瀬 聖子, 山道 茜, 鈴木 美穂, 勝島 啓佑, 石田 高司, 飯田 真介, 近藤 豊

    日本癌学会総会記事   77回 巻   頁: 760 - 760   2018年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

  48. PD-1 Inhibitor Therapy in Adult T-Cell Leukemia–Lymphoma. 査読有り

    Ishitsuka K, Utsunomiya A, Ishida T

    The New England journal of medicine   379 巻 ( 7 ) 頁: 695 - 696   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:New England Journal of Medicine  

    DOI: 10.1056/NEJMc1807852

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  49. Human T-cell lymphotropic/leukemia virus type 1 (HTLV-1) Tax-specific T-cell exhaustion in HTLV-1-infected individuals. 査読有り

    Masaki A, Ishida T, Suzuki S, Ito A, Narita T, Kinoshita S, Ri M, Kusumoto S, Komatsu H, Inagaki H, Ueda R, Iida S

    Cancer science   109 巻 ( 8 ) 頁: 2383 - 2390   2018年8月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    Adult T-cell leukemia/lymphoma (ATL) is caused by Human T-cell lymphotropic/leukemia virus type 1 (HTLV-1), and a higher HTLV-1 provirus load in PBMC is a risk factor for ATL development. Here, we document a significant inverse correlation between the function of HTLV-1 Tax-specific CTL (Tax-CTL), as assessed by ex vivo cytokine production in response to cognate peptide, and the HTLV-1 provirus load in PBMC in both HTLV-1 asymptomatic carriers (AC) (Spearman rank correlation coefficient [Rs] = −0.494, P =.037, n = 18) and ATL patients (Rs = −0.774, P =.001, n = 15). There was also a significant correlation between the HTLV-1 provirus load and the percentage of PD-1-positive Tax-CTL in both HTLV-1 AC (Rs = 0.574, P =.013) and ATL patients (Rs = 0.676, P =.006). Furthermore, the percentage of PD-1-positive Tax-CTL was inversely correlated with their function in HTLV-1 AC (Rs = −0.542, P =.020), and ATL patients (Rs = −0.639, P =.010). These findings indicate that the function of Tax-CTL decreased as their programmed cell death protein 1 (PD-1) levels increased, parallel to the increased HTLV-1 provirus load in PBMC. We propose that functional Tax-CTL are crucial for determining the HTLV-1 provirus load in PBMC, not only in HTLV-1 AC, but also in ATL, and that PD-1 expression levels are reliable markers of Tax-CTL function. Thus, modulating the immunological equilibrium between Tax-CTL and HTLV-1-infected cells to achieve dominance of functional effectors could represent an ideal strategy for controlling HTLV-1-associated disease.

    DOI: 10.1111/cas.13654

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  50. Potent antitumor effect of combination therapy with sub-optimal doses of Akt inhibitors and pomalidomide plus dexamethasone in multiple myeloma. 査読有り

    Kinoshita S, Ri M, Kanamori T, Aoki S, Yoshida T, Narita T, Totani H, Ito A, Kusumoto S, Ishida T, Komatsu H, Iida S

    Oncology letters   15 巻 ( 6 ) 頁: 9450 - 9456   2018年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Oncology Letters  

    Afuresertib (AFU), a novel inhibitor of the serine/threonine kinase AKT, has clinical efficacy as a mono­therapy against hematological malignancies and is expected to be used in combination with standard therapies for multiple myeloma (MM). To develop a more effective and less toxic combination of immunomodulatory drugs (IMiDs) for therapy, the antitumor effect of sub-optimal doses of AFU, pomalidomide plus dexamethasone (PD), and the AFU-PD combination on MM cells were examined in the present study. Two MM cell lines, XG‑7 and U266, with low sensitivity to both PD and AFU monotherapies, were subjected to these combinations and analyzed. Although the cell lines showed a slight reduction in viability with the sub‑optimal doses of each monotherapy, the combination of the treatments resulted in a reduction in cell viability and the progression of apoptosis. Co-treatment with sub-optimal doses of PD and AFU enhanced caspase activation and highly suppressed the expression of IKZF1 and IKZF3. In addition, this combination promoted the dephosphorylation and stabilization of 4EBP1, an inhibitor of eIF4E activation, which led to the impairment of eIF4E-mediated translational activity. Furthermore, AFU showed a sufficient inhibitory effect on the phosphorylation of FOXO1, a tumor suppressor, in monotherapy or in combination with PD, which may be attributable to the activation of FOXO1, the subsequent inhibition of tumor growth, and the induction of cell death. In conclusion, the combination therapy with sub-optimal doses of PD and AFU exhibited potent antitumor activity in MM cells and may provide a novel strategy for the treatment of patients who experienced intolerable toxicity or insufficient response during IMiD therapy.

    DOI: 10.3892/ol.2018.8501

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  51. Targeting General Transcriptional Machinery as a Therapeutic Strategy for Adult T-Cell Leukemia. 査読有り

    Wong RWJ, Ishida T, Sanda T

    Molecules (Basel, Switzerland)   23 巻 ( 5 )   2018年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3390/molecules23051057

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  52. Risk Assessment in Adult T Cell Leukemia/Lymphoma Treated with Allogeneic Hematopoietic Stem Cell Transplantation. 査読有り

    Yoshimitsu M, Tanosaki R, Kato K, Ishida T, Choi I, Takatsuka Y, Fukuda T, Eto T, Hidaka M, Uchida N, Miyamoto T, Nakashima Y, Moriuchi Y, Nagafuji K, Miyazaki Y, Ichinohe T, Takanashi M, Atsuta Y, Utsunomiya A, ATL Working Group of the Japan Society for Hematopoietic Cell Transplantation.

    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation   24 巻 ( 4 ) 頁: 832 - 839   2018年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Biology of Blood and Marrow Transplantation  

    Disease status at allogeneic hematopoietic cell transplantation (HCT) is an important pretransplant prognostic factor of HCT in adult T cell leukemia/lymphoma (ATL); however, other prognostic factors, including comorbidities, were not predictive in small cohort analyses. Several scoring systems (HCT-specific comorbidity index [HCT-CI]/modified European Group for Blood and Marrow Transplantation risk score [mEBMT]) have been adopted to predict HCT outcomes in other hematologic malignancies. We retrospectively evaluated HCT-CI and mEBMT to predict nonrelapse mortality (NRM) in 824 ATL patients registered in the Japan Society for Hematopoietic Cell Transplantation TRUMP database, from 2008 until 2013. A higher HCT-CI was associated with greater NRM when comparing HCT-CI 0 versus HCT-CI 1 to 3 and HCT-CI 0 versus HCT-CI ≥ 4. A higher mEBMT score was not associated with higher NRM when comparing mEBMT 0 to 3 with 4 to 6. Because ATL patients are older and consequently at risk of additional complications, we developed an optimized prognostic index for ATL (ATL-HCT-PI) using known risk factors: age, HCT-CI, and donor–recipient sex combination. The ATL-HCT-PI scores effectively predicted the 2-year NRM (22.0%, 27.7%, and 44.4%, respectively). Therefore, the newly developed ATL-HCT-PI, in combination with other risk factors, is more useful for predicting NRM in HCT for ATL patients.

    DOI: 10.1016/j.bbmt.2017.11.005

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  53. Dasatinib-associated reversible demyelinating peripheral polyneuropathy in a case of chronic myeloid leukemia.

    Ishida T, Akagawa N, Miyata T, Tominaga N, Iizuka T, Higashihara M, Suzuki T, Miyazaki K

    International journal of hematology   107 巻 ( 3 ) 頁: 373-377   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/s12185-017-2339-5

    PubMed

  54. Potent anti-tumor activity of a syringolin analog in multiple myeloma: a dual inhibitor of proteasome activity targeting β2 and β5 subunits. 査読有り

    Yoshida T, Ri M, Kanamori T, Aoki S, Ashour R, Kinoshita S, Narita T, Totani H, Masaki A, Ito A, Kusumoto S, Ishida T, Komatsu H, Kitahata S, Chiba T, Ichikawa S, Iida S

    Oncotarget   9 巻 ( 11 ) 頁: 9975 - 9991   2018年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Oncotarget  

    Proteasome inhibitors (PI), mainly targeting the β5 subunit of the 20S proteasome, are widely used in the treatment of multiple myeloma (MM). However, PI resistance remains an unresolved problem in the therapy of relapsed and refractory MM. To develop a new PI that targets other proteasome subunits, we examined the anti-MM activity of a novel syringolin analog, syringolog-1, which inhibits the activity of both the β5 and β2 subunits. Syringolog-1 exhibited marked cytotoxicity against various MM cell lines and anti-tumor activity towards bortezomib (Btz)-resistant MM cells through the dual inhibition of chymotrypsin-like (β5 subunit) and trypsin-like (β2 subunit) activities. MM cells, including Btz-resistant cells, showed elevated CHOP and NOXA expression after syringolog-1 treatment, indicating the induction of excessive endoplasmic reticulum stress during syringolog-1 treatment. Similar activities of syringolog-1 were also observed in freshly prepared MM cells derived from patients. To clarify the anti-tumor mechanism of dual inhibition of both the β5 and β2 subunits of the proteasome, PSMB5 and PSMB7 were co-inhibited in MM cells. This resulted in increased apoptosis of MM cells accompanied by accumulation of ubiquitinated proteins compared to inhibition of either PSMB7 or PSMB5 alone, indicating an enhanced effect by double inhibition of β2 and β5 activities. In conclusion, this syringolin analog, a dual inhibitor of proteasome β2 and β5 activities, exhibited potent anti-tumor effects on MM cells and may be useful for overcoming Btz-resistance in the treatment of MM.

    DOI: 10.18632/oncotarget.24160

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  55. Cognitive dysfunction among newly diagnosed older patients with hematological malignancy: frequency, clinical indicators and predictors. 査読有り

    Aiki S, Okuyama T, Sugano K, Kubota Y, Imai F, Nishioka M, Ito Y, Iida S, Komatsu H, Ishida T, Kusumoto S, Akechi T

    Japanese journal of clinical oncology   48 巻 ( 1 ) 頁: 61 - 67   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Japanese Journal of Clinical Oncology  

    Background: Medical staffoften overlook or underestimate the presence or severity of cognitive dysfunction. The purpose of this study was to clarify the frequency, clinical indicators and predictors of cognitive dysfunction among newly diagnosed older patients with hematologic malignancy receiving first-line chemotherapy. Methods: Patients aged 65 years or over with a primary diagnosis of malignant lymphoma or multiple myeloma were consecutively recruited. Cognitive dysfunction was evaluated using the Mini-Mental State Examination (MMSE) twice: before starting chemotherapy (T1) and 1 month later (T2). Participants also underwent a comprehensive geriatric assessment at T1. Potential clinical indicators that were associated with cognitive dysfunction were explored via cross-sectional analysis at T1. Predictors of cognitive dysfunction at T2 were also investigated among patients without cognitive dysfunction at T1. Results: A total of 145 participants participated in the study; cognitive dysfunction at T1 was present in 20%. Multivariate analysis demonstrated that lower educational attainment and poorer instrumental activities of daily living were significant clinical indicators of cognitive dysfunction. Among 99 patients who did not have cognitive dysfunction at T1 and underwent cognitive assessment at T2, 7% developed dysfunction. Subjective perception of difficulty remembering at T1 was the only factor which significantly predicted new-onset cognitive dysfunction at T2. Conclusions: The prevalence rate of cognitive dysfunction was non-negligible among older patients with hematologic malignancy before and immediately after initial chemotherapy. Attention to the clinical indicators and predictors found in this study may provide facilitate the identification of cognitive dysfunction in patients with cancer.

    DOI: 10.1093/jjco/hyx159

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  56. Clinical significance of tryptophan catabolism in Hodgkin lymphoma. 査読有り

    Masaki A, Ishida T, Maeda Y, Ito A, Suzuki S, Narita T, Kinoshita S, Takino H, Yoshida T, Ri M, Kusumoto S, Komatsu H, Inagaki H, Ueda R, Choi I, Suehiro Y, Iida S

    Cancer science   109 巻 ( 1 ) 頁: 74 - 83   2018年1月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    Indoleamine 2,3-dioxygenase 1 (IDO) is an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway. The purpose of the present study was to determine the clinical significance of Trp catabolism in newly diagnosed Hodgkin lymphoma (HL) patients. We quantified serum Trp and Kyn in 52 HL patients, and analyzed their associations with different clinical parameters including serum soluble CD30 concentration. The IDO expression was evaluated in the patients’ affected lymph nodes. The cohort comprised 22 male and 30 female patients (age range, 15-81 years; median, 45 years), with a 5-year overall survival (OS) of 88.6%. The OS was significantly shorter for patients with a high Kyn/Trp ratio (OS at 5 years, 60.0% vs 92.2%), for those with stage IV disease, and for those with lymphocytopenia (<600/mm3 and/or <8% white blood cell count). The latter two parameters are components of the international prognostic score for advanced HL. In contrast, there were no significant differences in OS according to age, serum albumin, hemoglobin, sex, white blood cell count, or serum soluble CD30 (≥ or <285.6 ng/mL). Multivariate analysis using the three variables stage, lymphocytopenia, and serum Kyn/Trp ratio showed that only the latter significantly affected OS. Indoleamine 2,3-dioxygenase 1 was produced by macrophages/dendritic cells, but not by HL tumor cells, and IDO levels determined by immunohistochemistry had a significant positive correlation with the serum Kyn/Trp ratio. In conclusion, quantification of serum Kyn and Trp is useful for predicting prognosis of individual HL patients.

    DOI: 10.1111/cas.13432

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  57. [Current status and future directions of ATL].

    Ishida T

    [Rinsho ketsueki] The Japanese journal of clinical hematology   59 巻 ( 10 ) 頁: 2136-2145   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.11406/rinketsu.59.2136

    PubMed

  58. [Sporadic late-onset nemaline myopathy with monoclonal gammopathy of undetermined significance mimicking POEMS syndrome]. 査読有り

    Kanamori T, Kusumoto S, Okita K, Hagiwara S, Kato C, Nakashima T, Murakami S, Narita T, Ito A, Ri M, Ishida T, Komatsu H, Matsukawa N, Iida S

    [Rinsho ketsueki] The Japanese journal of clinical hematology   59 巻 ( 2 ) 頁: 161 - 166   2018年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:一般社団法人 日本血液学会  

    <p>40歳,女性。1年前より全身性の皮疹,肝脾腫,甲状腺機能低下およびIgG-λ型M蛋白を認めるも,明らかな末梢神経障害の所見を指摘できず,POEMS症候群の確定診断に至らなかった。また,後頸部中心の筋力低下を伴っていた。経過観察中に呼吸筋障害によるII型呼吸不全が進行,NPPV導入となった。POEMS症候群による末梢神経障害が原因と判断し,全身化学療法を開始するも,奏効せず,人工呼吸器管理となった。その後,M蛋白を伴う,孤発性成人発症型ネマリンミオパチー(SLONM with MGUS)を疑い,大腿部の筋生検にてネマリン小体を認め,SLONM with MGUSの確定診断に至った。本症例は呼吸不全の進行により,大量メルファラン併用自家末梢血幹細胞移植療法は施行できなかった。SLONM with MGUSは極めてまれな疾患であるが,致死的なM蛋白関連疾患として認識すべきである。</p>

    DOI: 10.11406/rinketsu.59.161

    PubMed

  59. Low expression of neural cell adhesion molecule, CD56, is associated with low efficacy of bortezomib plus dexamethasone therapy in multiple myeloma. 査読有り

    Yoshida T, Ri M, Kinoshita S, Narita T, Totani H, Ashour R, Ito A, Kusumoto S, Ishida T, Komatsu H, Iida S

    PloS one   13 巻 ( 5 ) 頁: e0196780   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PLoS ONE  

    Bortezomib (Btz) is an active agent used to treat multiple myeloma (MM). Not all patients who receive Btz-containing therapy show a favorable response. Interaction of cellular adhesion molecules with MM and bone marrow stromal cells is crucial for the survival of MM cells. However, little is known about the role of these molecules in the sensitivity of MM to Btz-containing therapy. Thus, we evaluated the correlation between the level of cellular adhesion molecules in MM cells and the efficacy of Btz plus dexamethasone (Bd) therapy. The expression of the neural cell adhesion molecule gene (NCAM, also known as CD56), ITGA4, CXCR4, and other genes were analyzed in 74 samples of primary MM cells collected from patients before they received Bd therapy. Of the eight genes tested, expression of NCAM was lower among patients who responded poorly to Bd therapy. In vitro expression of NCAM induced by transfection of MM cells enhanced their sensitivity to Btz treatment by causing accumulation of polyubiquitinated proteins. Our results indicate that expression of NCAM is associated with better response to Btz treatment and is a promising candidate biomarker for predicting response to therapies involving Btz.

    DOI: 10.1371/journal.pone.0196780

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  60. Pre‐ and posttransplant use of mogamulizumab in patients with aggressive adult T‐cell leukemia lymphoma: A statement from key opinion leaders in Japan. 査読有り

    Fuji S, Kato K, Nakano N, Ishida T, Ishitsuka K, Choi I, Matsuoka KI, Utsunomiya A

    Adv Cell Gene Ther.   ( 1 ) 頁: e5   2018年

  61. Epidemiological and clinical features of adult T-cell leukemia–lymphoma in Japan, 2010–2011: A nationwide survey 査読有り 国際誌

    Nosaka K., Iwanaga M., Imaizumi Y., Ishitsuka K., Ishizawa K., Ishida Y., Amano M., Ishida T., Uike N., Utsunomiya A., Ohshima K., Kawai K., Tanaka J., Tokura Y., Tobinai K., Watanabe T., Uchimaru K., Tsukasaki K.

    Cancer Science   108 巻 ( 12 ) 頁: 2478 - 2486   2017年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    Adult T-cell leukemia–lymphoma (ATL) is a mature T-cell malignancy associated with human T-cell leukemia virus type 1 (HTLV-1) infection. Japan is the most endemic country for HTLV-1 and ATL in the world. Recent nationwide studies of Japanese blood donors reported that HTLV-1 carriers spread from endemic areas to non-endemic areas. Therefore, the latest information on nationwide epidemiological and clinical data for ATL is necessary to guide clinical practice. We undertook a multicenter, hospital-based survey of newly diagnosed ATL patients from 2010 to 2011. A total of 996 patients with ATL were registered from 126 hospitals across Japan. Of those, 922 (487 men and 435 women) were included in the analysis. The median age at diagnosis was 68 years (interquartile range, 60–75 years). Overall, 67.2% of ATL was diagnosed in the Kyushu–Okinawa area. The most common subtype was acute (49.5%), followed by lymphoma (25.7%), chronic (14.2%), and smoldering (10.6%). Lymphoma type was more prevalent in men (60%), whereas chronic was more prevalent in women (60%). Half of patients with lymphoma type were aged over 70 years, whereas one-third of patients with the chronic type were aged under 60 years. All of these characteristics were different from those of the previous nationwide surveys in the 1980s and 1990s. This survey clarified that half of current patients with ATL are aged over 68 years who were unable to receive intensive cytotoxic therapies. New less toxic agents for aged patients and further strategies to prevent the development of ATL from HTLV-1 carrier status are needed.

    DOI: 10.1111/cas.13398

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  62. Enhancer profiling identifies critical cancer genes and characterizes cell identity in adult T-cell leukemia. 査読有り

    Wong RWJ, Ngoc PCT, Leong WZ, Yam AWY, Zhang T, Asamitsu K, Iida S, Okamoto T, Ueda R, Gray NS, Ishida T, Sanda T

    Blood   130 巻 ( 21 ) 頁: 2326 - 2338   2017年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blood  

    A number of studies have recently demonstrated that super-enhancers, which are large cluster of enhancers typically marked by a high level of acetylation of histone H3 lysine 27 and mediator bindings, are frequently associated with genes that control and define cell identity during normal development. Super-enhancers are also often enriched at cancer genes in various malignancies. The identification of such enhancers would pinpoint critical factors that directly contribute to pathogenesis. In this study, we performed enhancer profiling using primary leukemia samples from adult T-cell leukemia/lymphoma (ATL), which is a genetically heterogeneous intractable cancer. Super-enhancers were enriched at genes involved in the T-cell activation pathway, including IL2RA/CD25, CD30, and FYN, in both ATL and normal mature T cells, which reflected the origin of the leukemic cells. Super-enhancers were found at several known cancer gene loci, including CCR4, PIK3R1, and TP73, in multiple ATL samples, but not in normal mature T cells, which implicated those genes in ATL pathogenesis. A small-molecule CDK7 inhibitor, THZ1, efficiently inhibited cell growth induced apoptosis and downregulated the expression of super-enhancer–associated genes in ATL cells. Furthermore, enhancer profiling combined with gene expression analysis identified a previously uncharacterized gene, TIAM2, that was associated with super-enhancers in all ATL samples, but not in normal T cells. Knockdown of TIAM2 induced apoptosis in ATL cell lines, whereas overexpression of this gene promoted cell growth. Our study provides a novel strategy for identifying critical cancer genes.

    DOI: 10.1182/blood-2017-06-792184

    Web of Science

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  63. Clinical Practice Recommendations on Indication and Timing of Hematopoietic Cell Transplantation in Mature T Cell and NK/T Cell Lymphomas: An International Collaborative Effort on Behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplantation. 査読有り

    Kharfan-Dabaja MA, Kumar A, Ayala E, Hamadani M, Reimer P, Gisselbrecht C, d'Amore F, Jantunen E, Ishida T, Bazarbachi A, Foss F, Advani R, Fenske TS, Lazarus HM, Friedberg JW, Aljurf M, Sokol L, Tobinai K, Tse E, Burns LJ, Chavez JC, Reddy NM, Suzuki R, Ahmed S, Nademanee A, Mohty M, Gopal AK, Fanale MA, Pro B, Moskowitz AJ, Sureda A, Perales MA, Carpenter PA, Savani BN

    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation   23 巻 ( 11 ) 頁: 1826 - 1838   2017年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Biology of Blood and Marrow Transplantation  

    Recognizing the significant biological and clinical heterogeneity of mature T cell and natural killer (NK)/T cell lymphomas, the American Society for Blood and Marrow Transplantation invited experts to develop clinical practice recommendations related to the role of autologous hematopoietic cell transplantation (auto-HCT) and allogeneic HCT (allo-HCT) for specific histological subtypes. We used the GRADE methodology to aid in moving from evidence to decision making and ultimately to generating final recommendations. Auto-HCT in front-line consolidation is recommended in peripheral T cell lymphoma not otherwise specified (PTCL-NOS), angioimmunoblastic T cell lymphoma (AITL), anaplastic large cell lymphoma–anaplastic lymphoma kinase (ALCL-ALK)-negative, NK/T cell (disseminated), enteropathy-associated T cell lymphoma (EATL), and hepatosplenic lymphomas. Auto-HCT in relapsed-sensitive disease is recommended for NK/T cell (localized and disseminated), EATL, subcutaneous panniculitis-like T cell, and ALCL-ALK–positive lymphomas. Auto-HCT is also recommended for PTCL-NOS, AITL, and ALCL-ALK–negative lymphomas if not performed as front-line therapy. Auto-HCT in refractory (primary or relapsed) disease is not recommended for any of the histological subtypes discussed. Allo-HCT in front-line consolidation is recommended for NK/T cell (disseminated), adult T cell leukemia/lymphoma (ATLL; acute and lymphoma type), and hepatosplenic lymphomas. Allo-HCT for relapsed-sensitive disease is recommended for PTCL-NOS, AITL, ALCL-ALK–negative, ALCL-ALK–positive, NK/T cell (localized and disseminated), ATLL (acute, lymphoma type, smoldering/chronic), mycosis fungoides/Sezary syndrome (advanced stage IIB-IVB or tumor stage/extracutaneous), EATL, subcutaneous panniculitis-like T cell, and hepatosplenic lymphoma. Allo-HCT in refractory (primary or relapsed refractory) disease is recommended for any aforementioned histological subtypes. Emerging novel therapies will likely be incorporated into the pretransplantation, peritransplantation, and post-transplantation algorithms (auto-HCT or allo-HCT) with the goals of optimizing efficacy and improving outcomes. We acknowledge that there are unique clinical scenarios not covered by these recommendations that may require individualized decisions.

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  64. Romidepsin in Japanese patients with relapsed or refractory peripheral T-cell lymphoma: a phase I/II and pharmacokinetics study. 査読有り

    Maruyama D, Tobinai K, Ogura M, Uchida T, Hatake K, Taniwaki M, Ando K, Tsukasaki K, Ishida T, Kobayashi N, Ishizawa K, Tatsumi Y, Kato K, Kiguchi T, Ikezoe T, Laille E, Ro T, Tamakoshi H, Sakurai S, Ohtsu T

    International journal of hematology   106 巻 ( 5 ) 頁: 655 - 665   2017年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Hematology  

    This phase I/II multicenter study evaluated romidepsin treatment in Japanese patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Patients aged ≥20 years received romidepsin via a 4-h intravenous infusion on days 1, 8, and 15 of each 28-day cycle. Phase I used a 3 + 3 design to identify any dose-limiting toxicity (DLT) for regimens of romidepsin 9 and 14 mg/m2. The primary endpoints for phase I and II were DLT and overall response rate (ORR), respectively. Intent-to-treat patients were those who received ≥1 romidepsin dose (PTCL, n = 48; CTCL, n = 2). In phase I, none of the patients (n = 3, 9 mg/m2; n = 6, 14 mg/m2) exhibited DLT. In phase II, 40 patients with PTCL were treated with 14 mg/m2 romidepsin. The most common treatment-emergent grade ≥3 adverse events were lymphopenia (74%), neutropenia (54%), leukopenia (46%), and thrombocytopenia (38%). Patients in phase II showed a 43% ORR, including 25% complete responses. Median progression-free survival was 5.6 months and median duration of response was 11.1 months. This phase I/II study identified a well-tolerated dose of romidepsin, with an acceptable toxicity profile and clinically meaningful efficacy in Japanese patients with relapsed/refractory PTCL. ClinicalTrials.gov Identifier NCT01456039.

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  65. Mogamulizumab for relapsed adult T-cell leukemia–lymphoma: Updated follow-up analysis of phase I and II studies 査読有り

    Ishida T., Utsunomiya A., Jo T., Yamamoto K., Kato K., Yoshida S., Takemoto S., Suzushima H., Kobayashi Y., Imaizumi Y., Yoshimura K., Kawamura K., Takahashi T., Tobinai K., Ueda R.

    Cancer Science   108 巻 ( 10 ) 頁: 2022 - 2029   2017年10月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Science  

    The present study sought to elucidate the prognosis of adult T-cell leukemia–lymphoma (ATL) patients receiving mogamulizumab, a defucosylated anti-CCR4 monoclonal antibody. Progression-free survival (PFS) and overall survival (OS) of ATL patients enrolled in two studies are herein updated, namely NCT00355472 (phase I study of mogamulizumab in relapsed patients with ATL and peripheral T-cell lymphoma) and NCT00920790 (phase II study for relapsed ATL). Of 13 patients with relapsed aggressive ATL in the phase I study, four (31%) survived >3 years. For 26 relapsed patients with aggressive ATL in the phase II study, median PFS was 5.2 months and 1-year PFS was 26%, whereas median OS was 14.4 months, and 3-year OS was 23%. For patients without a rash or who developed a grade 1 rash only, median PFS was 0.8 months, and 1-year PFS was zero, with a median OS of 6.0 months, and 3-year OS of 8%. In contrast, for patients who developed a rash ≥grade 2, median PFS was 11.7 months, and 1-year PFS was 50%, with a median OS of 25.6 months, and 3-year OS of 36%. Thus, we conclude that mogamulizumab monotherapy may improve PFS and OS in some patients with relapsed aggressive ATL, especially those who develop a skin rash as a moderate immune-related adverse event. Therefore, further investigation is warranted to validate the present observations and to clarify the mechanisms involved in the activity of mogamulizumab.

    DOI: 10.1111/cas.13343

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  66. Novel monitoring of hepatitis B reactivation based on ultra-high sensitive hepatitis B surface antigen assay. 査読有り

    Shinkai N, Kusumoto S, Murakami S, Ogawa S, Ri M, Matsui T, Tamori A, Toyoda H, Ishida T, Iida S, Tanaka Y

    Liver international : official journal of the International Association for the Study of the Liver   37 巻 ( 8 ) 頁: 1138 - 1147   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Liver International  

    Background & Aims: Occult hepatitis B virus (HBV) infection should be evaluated before systemic chemotherapy to prevent HBV reactivation-related hepatitis. We investigated HBV reactivation using high sensitivity HB surface antigen (HBsAg) chemiluminescent enzyme immunoassay (HBsAg-HQ) and ultra-high sensitive HBsAg assay employing a semi-automated immune complex transfer chemiluminescence enzyme technique (ICT-CLEIA). Methods: Of 120 HBV-resolved patients with haematological malignancy receiving systemic chemotherapy from 2012 to 2015 in our hospital, 13 patients had HBV DNA reactivation (in 12/13 patients HBV DNA became quantifiable) according to HBV DNA monitoring. These patients were applied for Architect HBsAg-QT (detection limit:50 mIU/mL), HBsAg-HQ (5 mIU/mL) and ICT-CLEIA (0.5 mIU/mL) using stored samples. Results: When HBV DNA was firstly quantifiable by regular HBV DNA monitoring, HBsAg-QT was detected in 1/12 patients (8%), HBsAg-HQ was detected in 4/12 patients (33%) and ICT-CLEIA was detected in all 12 patients (100%), suggesting that the sensitivity of ICT-CLEIA was comparable to that of HBV DNA quantification. Interestingly, two patients were HBsAg positive by ICT-CLEIA before HBV DNA became detectable. Median difference of detectable point between HBV DNA and ICT-CLEIA was zero (range from −28 to 56 days), while median delay by HBsAg-QT or HBsAg-HQ was 52.5 days after HBV DNA became detectable. Although anti-HBs titres were high (131.9 mIU, 80.4 mIU) in two patients with escape mutations (Saa126V, Saa145R), HBsAg by ICT-CLEIA and HBV DNA were detectable concurrently. Conclusions: ICT-CLEIA is a novel assay for HBV monitoring to prevent hepatitis caused by HBV reactivation.

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  67. Does cognitive decline decrease health utility value in older adult patients with cancer? 査読有り

    Akechi T, Aiki S, Sugano K, Uchida M, Yamada A, Komatsu H, Ishida T, Kusumoto S, Iida S, Okuyama T

    Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society   17 巻 ( 3 ) 頁: 149 - 154   2017年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Psychogeriatrics  

    Aim: Cognitive decline is common among older adults with cancer. The present study aimed to investigate the impact of cognitive decline on health utility value in older adults suffering from cancer. Methods: Consecutive patients aged 65 years or older with a primary diagnosis of malignant lymphoma or multiple myeloma were recruited. Patients were asked to complete the EuroQoL-5 (EQ-5D) scale to measure health utility and the Mini-Mental State Examination to assess cognitive decline. The potential impact of cognitive decline was investigated with univariate analysis. A multivariate regression analysis was conducted to control for potential confounding factors. Results: Complete data were obtained from 87 patients, 29% of whom had cognitive decline. The mean ± SE EQ-5D score for patients with cognitive decline was significantly lower than that for those without cognitive decline (0.67 ± 0.04 vs 0.79 ± 0.03, t = 2.38, P = 0.02). However, multiple regression analysis showed that cognitive decline was not significantly associated with EQ-5D scores. Female sex and lower performance scores (worse physical condition) were significantly associated with EQ-5D scores. Conclusions: Cognitive decline may be involved in decreased health utility value in older adult patients with cancer. However, this effect does not seem to be independent, and the patient's physical condition may be a relevant confounding factor.

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  68. Randomized phase II study of nab-paclitaxel as first-line chemotherapy in patients with HER2-negative metastatic breast cancer

    Tamura K., Inoue K., Masuda N., Takao S., Kashiwaba M., Tokuda Y., Iwata H., Yamamoto N., Aogi K., Saeki T., Nakayama T., Sato N., Toyama T., Ishida T., Arioka H., Saito M., Ohno S., Yamauchi H., Yamada K., Watanabe J., Ishiguro H., Fujiwara Y.

    Cancer Science   108 巻 ( 5 ) 頁: 987 - 994   2017年5月

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    記述言語:日本語   出版者・発行元:Cancer Science  

    Weekly administration of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) has been shown to be a safe and effective treatment for metastatic breast cancer (MBC) in clinical studies. We conducted a multicenter, randomized, open-label phase II study to compare the efficacy and safety of weekly nab-paclitaxel and docetaxel in Japanese patients with human epidermal growth factor receptor 2-negative MBC. The primary endpoint was progression-free survival (PFS). Patients were randomized to receive nab-paclitaxel (150 mg/m2 nab-paclitaxel once per week for 3 of 4 weeks; n = 100) or docetaxel (75 mg/m2 docetaxel every 3 weeks; n = 100). The median PFS by independent radiologist assessment was 9.8 months (90% confidence interval [CI]: 8.5–11.2) for nab-paclitaxel and 11.2 months (90% CI: 8.4–13.8) for docetaxel (hazard ratio: 1.25, P = 0.363), and the median overall survival was 42.4 months and 34.0 months, respectively. The overall response rate was 56.1% for nab-paclitaxel and 52.5% for docetaxel. Adverse events in both treatment arms were similar to previous reports. Neutropenia was the most common adverse event in both arms, with 35.0% of patients in the nab-paclitaxel arm and 89.0% in the docetaxel arm experiencing grade 4 neutropenia. Grade 3 peripheral sensory neuropathy occurred in 22.0% of patients in the nab-paclitaxel and 5.0% in the docetaxel arm. In this study, although weekly nab-paclitaxel 150 mg/m2 did not show superiority in PFS compared with docetaxel, efficacy outcomes were similar in patients treated with weekly nab-paclitaxel and docetaxel.

    DOI: 10.1111/cas.13221

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  69. Carfilzomib, lenalidomide and dexamethasone in patients with heavily pretreated multiple myeloma: A phase 1 study in Japan

    Suzuki K.

    Cancer Science   108 巻 ( 3 ) 頁: 461-468   2017年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1111/cas.13166

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  70. Novel and highly sensitive immunoassay for total hepatitis B surface antigen, including that complexed with hepatitis B surface antibody

    Matsumoto A.

    Journal of Gastroenterology   52 巻 ( 3 ) 頁: 376-384   2017年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/s00535-016-1244-7

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  71. Anti-Myeloma Activity of a Syringolin Analog: A Dual 20S Proteasome Inhibitor of Beta 2 and 5 Subunits 査読有り

    Takashi Yoshida, Masaki Ri, Shiori Kinoshita, Tomoko Narita, Haruhito Totani, Reham Ashour, Ayako Masaki, Asahi Ito, Shigeru Kusumoto, Takashi Ishida, Hirokazu Komatsu, Satoshi Ichikawa, Shinsuke Iida

    BLOOD   128 巻 ( 22 )   2016年12月

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    記述言語:英語   出版者・発行元:AMER SOC HEMATOLOGY  

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  72. Quantitative PCR for HTLV-1 provirus in adult T-cell leukemia/lymphoma using paraffin tumor sections. 査読有り

    Kato J, Masaki A, Fujii K, Takino H, Murase T, Yonekura K, Utsunomiya A, Ishida T, Iida S, Inagaki H

    Pathology international   66 巻 ( 11 ) 頁: 618 - 621   2016年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Pathology International  

    Detection of HTLV-1 provirus using paraffin tumor sections may assist the diagnosis of adult T-cell leukemia/lymphoma (ATLL). For the detection, non-quantitative PCR assay has been reported, but its usefulness and limitations remain unclear. To our knowledge, quantitative PCR assay using paraffin tumor sections has not been reported. Using paraffin sections from ATLLs and non-ATLL T-cell lymphomas, we first performed non-quantitative PCR for HTLV-1 provirus. Next, we determined tumor ratios and carried out quantitative PCR to obtain provirus copy numbers. The results were analyzed with a simple regression model and a novel criterion, cut-off using 95 % rejection limits. Our quantitative PCR assay showed an excellent association between tumor ratios and the copy numbers (r = 0.89, P < 0.0001). The 95 % rejection limits provided a statistical basis for the range for the determination of HTLV-1 involvement. Its application suggested that results of non-quantitative PCR assay should be interpreted very carefully and that our quantitative PCR assay is useful to estimate the status of HTLV-1 involvement in the tumor cases. In conclusion, our quantitative PCR assay using paraffin tumor sections may be useful for the screening of ATLL cases, especially in HTLV-1 non-endemic areas where easy access to serological testing for HTLV-1 infection is limited.

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  73. EBV関連T細胞およびNK細胞リンパ増殖性疾患の治療標的としてのCDK9(CDK9 as a target for treatment in EBV-associated T- and NK-cell lymphoproliferative diseases) 査読有り

    Kinoshita Shiori, Ishida Takashi, Narita Tomoko, Ito Asahi, Masaki Ayako, Suzuki Susumu, Takino Hisashi, Yoshida Takashi, Ri Masaki, Kusumoto Shigeru, Komatsu Hirokazu, Shimizu Norio, Inagaki Hiroshi, Scholz Arne, Ince Stuart, Ueda Ryuzo, Iida Shinsuke

    臨床血液   57 巻 ( 9 ) 頁: 1541 - 1541   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:(一社)日本血液学会-東京事務局  

  74. The value of serum Wisteria floribunda agglutinin-positive human Mac-2-binding protein as a predictive marker for hepatitis C virus-related complications after systemic chemotherapy. 査読有り

    Totani H, Kusumoto S, Tanaka Y, Suzuki N, Hagiwara S, Kinoshita S, Iio E, Ito A, Ri M, Ishida T, Komatsu H, Iida S

    International journal of hematology   104 巻 ( 3 ) 頁: 384 - 391   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Hematology  

    Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA+-M2BP) was developed recently as a predictive marker of progression to liver fibrosis and hepatocellular carcinoma (HCC) in patients seropositive for hepatitis C virus (HCV). We retrospectively analyzed 16 HCV-seropositive patients who received systemic chemotherapy for hematologic malignancies to evaluate the usefulness of WFA+-M2BP for predicting HCV-related complications. These were defined as the onset of significant liver damage (LD) with increased HCV RNA levels, leading to interrupted or discontinued chemotherapy or the occurrence of HCC after chemotherapy. Baseline WFA+-M2BP levels were determined using preserved serum samples. The median level of WFA+-M2BP was 1.59 [cutoff index (C.O.I.) value range 0.38–6.66]. With a median follow-up of 623 days (range 120–2404), LD and HCC were observed in three and two patients, respectively. Detectable HCV RNA and WFA+-M2BP ≥2.0 C.O.I. at baseline were identified as risk factors for these HCV-related complications (P = 0.034 and P = 0.005, respectively). The sensitivity, specificity, and positive and negative predictive values of the WFA+-M2BP level (cutoff point: 2.0 C.O.I.) for the occurrence of HCV-related complications were 100.0, 81.8, 71.4, and 100.0 %, respectively. WFA+-M2BP may be a useful marker for the prediction of HCV-related complications in HCV-seropositive patients following systemic chemotherapy.

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  75. Multiple allogeneic progenitors in combination function as a unit to support early transient hematopoiesis in transplantation.

    Ishida T, Takahashi S, Lai CY, Nojima M, Yamamoto R, Takeuchi E, Takeuchi Y, Higashihara M, Nakauchi H, Otsu M

    The Journal of experimental medicine   213 巻 ( 9 ) 頁: 1865 - 80   2016年8月

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    記述言語:英語  

    DOI: 10.1084/jem.20151493

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  76. Effects of first-line chemotherapy on natural killer cells in adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma. 査読有り

    Ogura M, Ishida T, Tsukasaki K, Takahashi T, Utsunomiya A

    Cancer chemotherapy and pharmacology   78 巻 ( 1 ) 頁: 199 - 207   2016年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Cancer Chemotherapy and Pharmacology  

    Purpose: Natural killer (NK) cells are well known to be the most important effector cells mediating antibody-dependent cellular cytotoxicity (ADCC) which is an important mechanism of action of antibody drugs. We evaluated the effects of chemotherapy on the cell number and activity of NK cells from patients who received the vincristine–cyclophosphamide–doxorubicin–prednisone (VCAP), doxorubicin–ranimustine–prednisone (AMP), and vindesine–etoposide–carboplatin–prednisone (VECP) (mLSG15) or mLSG15-like (-L) regimen, which is one of the standard of cares for newly diagnosed adult T-cell leukemia–lymphoma (ATL), or the cyclophosphamide–doxorubicin–vincristine–prednisone (CHOP) or CHOP-L regimen which is another standard of care for ATL and peripheral T-cell lymphoma (PTCL). Methods: The number of lymphocytes and NK cells, and NK cell activity, were assessed using flow cytometry and a 51Cr release assay, respectively. Results: A total of 26 patients with untreated ATL or PTCL were enrolled, and blood samples from 25 patients were evaluable. NK cell number in ATL decreased after mLSG15/-L treatment, and the degree of decrease in the NK cell number was more prominent just before VECP therapy (Day 15–17 of each cycle) than just before VCAP therapy (Day 1 of each cycle). The NK cell number in ATL after CHOP/-L treatment also decreased. Interestingly, the NK cell activity showed a tendency to increase after the treatment. NK cell number in PTCL did not decrease by CHOP/-L regimen, but the activity was slightly decreased after the treatment. Conclusions: These results indicate that the effects of chemotherapeutic agents on NK cells vary according to the disease type and intensity of chemotherapy.

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  77. Current status of immunotherapy. 査読有り

    Suzuki S, Ishida T, Yoshikawa K, Ueda R

    Japanese journal of clinical oncology   46 巻 ( 3 ) 頁: 191 - 203   2016年3月

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    記述言語:英語   出版者・発行元:Japanese Journal of Clinical Oncology  

    The successful use of immune checkpoint inhibitors has been big breakthrough in the development of cancer immunotherapy. Anti-CTLA-4 monoclonal antibody, ipilimumab, is the first-approved immune checkpoint inhibitor and has shown durable objective responses for advanced melanoma beyond the effect of dacarbazine. Anti-PD-1 monoclonal antibodies, nivolumab and pembrolizumab, are other immune checkpoint inhibitors that have demonstrated more effective results than conventional drugs in clinical trials for a variety of advanced solid tumors including melanoma, non-small cell lung carcinoma and renal carcinoma. These studies have indicated that the enhancement of anti-cancer immunity by controlling the immune suppressive environment in cancer tissues is an important issue for the development of cancer immune-therapy. Accordingly, in recent years, the enthusiasm for research of cancer immunology has shifted to studies regarding the formation of the immune suppressive environment, immune suppression mechanisms in cancer tissues and the molecules and cells involved in these pathways. Novel findings from these studies might lead to the development of cancer immunotherapy based on control of the immune suppressive environment.

    DOI: 10.1093/jjco/hyv201

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  78. Phase I study of once weekly treatment with bortezomib in combination with lenalidomide and dexamethasone for relapsed or refractory multiple myeloma. 査読有り

    Totani H, Ri M, Kato C, Nakashima T, Suzuki N, Hagiwara S, Kanamori T, Murakami S, Masuda A, Kinoshita S, Yoshida T, Narita T, Ito A, Kusumoto S, Ishida T, Komatsu H, Iida S

    International journal of hematology   103 巻 ( 3 ) 頁: 316 - 321   2016年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Hematology  

    Proteasome inhibitors (PIs) in combination with immunomodulatory drugs (IMiDs) have been shown to be effective against relapsed/refractory multiple myeloma (RRMM). To determine the optimal dosing schedule of once weekly bortezomib (BTZ) combined with lenalidomide (LEN) and dexamethasone (DEX), especially in the outpatient setting, we conducted a phase I dose escalation study. A 21-day cycle of BTZ 1.3 mg/m2 on days 1 and 8, LEN 10 mg/day (cohort 1) or 15 mg/day (cohort 2) on days 1–14, and DEX 20 mg/day on days 1, 2, 8, and 9 was administered. Three patients were enrolled in each cohort. No dose-limiting toxicity was observed in either cohort. Although hematological toxicities estimated as >grade 3 were common, non-hematological toxicities of grade 3 or higher were rare. Two cases of newly diagnosed peripheral neuropathy (PN) were observed, while no grade 3/4 PN was observed. Two patients achieved partial response and two achieved stable disease. The recommended doses of BTZ and LEN were determined to be 1.3 mg/m2 and 15 mg, respectively. Combination therapy of once weekly BTZ with LEN and DEX was well tolerated and shows promise as a regimen for patients with RRMM previously treated with both PIs and IMiDs.

    DOI: 10.1007/s12185-015-1925-7

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  79. Labial salivary gland biopsy for diagnosing immunoglobulin light chain amyloidosis: a retrospective analysis. 査読有り

    Suzuki T, Kusumoto S, Yamashita T, Masuda A, Kinoshita S, Yoshida T, Takami-Mori F, Takino H, Ito A, Ri M, Ishida T, Komatsu H, Ueda M, Ando Y, Inagaki H, Iida S

    Annals of hematology   95 巻 ( 2 ) 頁: 279 - 285   2016年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Annals of Hematology  

    Our goal was to evaluate the usefulness of labial salivary gland (LSG) biopsy for diagnosing immunoglobulin light chain (AL) amyloidosis, by comparing bone marrow and skin biopsies in the same patient population. This retrospective study included 34 consecutive patients who showed evidence of monoclonal proteins and symptoms considered to be due to amyloidosis, and who underwent a tissue biopsy from LSG between January 2005 and December 2012 at Nagoya City University Hospital. All samples of superficial tissues, including LSG, bone marrow, and skin, were independently evaluated as having amyloid deposits by a central review, which was blind to clinical information. An AL amyloidosis diagnosis was based on evidence of amyloid deposition in any biopsied tissue. Eighteen patients were diagnosed with AL amyloidosis. The sensitivity for detecting amyloid deposition was highest in biopsies of LSG at 89 %, followed by 77 % for bone marrow, and 72 % for skin. Amyloid deposition was detected in at least one superficial tissue of all the 18 patients. An LSG biopsy may be appropriate as a first-choice procedure to diagnose AL amyloidosis. Multiple biopsies of superficial tissues, including LSG, bone marrow, and skin, are recommended to increase the sensitivity for diagnosing AL amyloidosis.

    DOI: 10.1007/s00277-015-2549-y

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  80. Fatal reactivation of hepatitis B virus infection in a patient with adult T-cell leukemia-lymphoma receiving the anti-CC chemokine receptor 4 antibody mogamulizumab. 査読有り

    Ifuku H, Kusumoto S, Tanaka Y, Totani H, Ishida T, Okada M, Murakami S, Mizokami M, Ueda R, Iida S

    Hepatology research : the official journal of the Japan Society of Hepatology   45 巻 ( 13 ) 頁: 1363 - 1367   2015年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Hepatology Research  

    We report an adult T-cell leukemia-lymphoma (ATL) patient suffering from fatal reactivation of hepatitis B virus (HBV) infection after treatment with the anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, mogamulizumab. HBV reactivation occurred without liver damage in this hepatitis B surface antigen (HBsAg) negative patient, who was seropositive for antibodies against the viral core and surface antigens at baseline, after two cycles of CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisolone) followed by six cycles of THP-COP regimen (cyclophosphamide, pirarubicin, vincristine and prednisolone). Unexpectedly, mogamulizumab monotherapy for relapsed CCR4 positive ATL induced sudden and fatal liver failure due to HBV reactivation, despite antiviral prophylaxis with entecavir. This clinical course may not only offer important suggestions to prevent critical HBV reactivation in HBsAg positive cancer patients who receive immune-enhancing drugs such as anti-CCR4 antibody, but also provide a clue to understanding the pathogenesis of HBV reactivation following systemic chemotherapy.

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  81. Lower expression of activating transcription factors 3 and 4 correlates with shorter progression-free survival in multiple myeloma patients receiving bortezomib plus dexamethasone therapy 査読有り

    Narita T., Ri M., Masaki A., Mori F., Ito A., Kusumoto S., Ishida T., Komatsu H., Iida S.

    Blood Cancer Journal   5 巻   2015年12月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blood Cancer Journal  

    Bortezomib (BTZ), a proteasome inhibitor, is widely used in the treatment of multiple myeloma (MM), but a fraction of patients respond poorly to this agent. To identify factors predicting the duration of progression-free survival (PFS) of MM patients on BTZ treatment, the expression of proteasome and endoplasmic reticulum (ER) stress-related genes was quantified in primary samples from patients receiving a combination of BTZ and dexamethasone (BD). Fifty-six MM patients were stratified into a group with PFS<6 months (n=33) and a second group with PFS≥6 months (n=23). Of the 15 genes analyzed, the expression of activating transcription factor 3 (ATF3) and ATF4 was significantly lower in patients with shorter PFS (P=0.0157 and P=0.0085, respectively). Chromatin immunoprecipitation analysis showed that these ATFs bind each other and transactivate genes encoding the pro-apoptotic transcription factors, CHOP and Noxa, which promote ER stress-associated apoptosis. When either ATF3 or ATF4 expression was silenced, MM cells partially lost sensitivity to BTZ treatment. This was accompanied by lower levels of Noxa, CHOP and DR5. Thus low basal expression of ATF3 and ATF4 may attenuate BTZ-induced apoptosis. Hence, ATF3 and ATF4 could potentially be used as biomarkers to predict efficacy of BD therapy in patients with MM.

    DOI: 10.1038/bcj.2015.98

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  82. Screening Performance for Frailty Among Older Patients With Cancer: A Cross-Sectional Observational Study of Two Approaches.

    Okuyama T, Sugano K, Iida S, Ishida T, Kusumoto S, Akechi T

    Journal of the National Comprehensive Cancer Network : JNCCN   13 巻 ( 12 ) 頁: 1525 - 31   2015年12月

     詳細を見る

    記述言語:英語   出版者・発行元:JNCCN Journal of the National Comprehensive Cancer Network  

    Objectives: To investigate the screening performance for frailty of the Vulnerable Elders Survey-13 (VES-13) and the 2-step approach consisting of the VES-13 plus the anhedonia (loss of interest or pleasure) item from Patient Health Questionnaire-9 (PHQ-9) among older patients with newly diagnosed cancer. Methods: This study involved 106 consecutive inpatients aged 65 years or older, newly diagnosed with malignant lymphoma or multiple myeloma, just before chemotherapy initiation. The participants were administered the VES-13, and also underwent a comprehensive geriatric assessment (CGA), including for depression and 6 other geriatric conditions, using validated measures, just before initiation of chemotherapy. We defined frailty as the presence of 2 or more geriatric conditions as determined by the CGA. Receiver operating characteristic analysis was performed. The 2-step screening approach was examined by post hoc analysis. Results: The average age of the subjects was 74 years. Among the 106 subjects, 50% met the criteria for frailty. Using a cutoff score of 2 to 3 on the VES-13, a sensitivity and negative predictive value (NPV) of 72% of the screening tool was obtained for the condition of frailty. When the second step of the screening, consisting of the VES-13 plus anhedonia, was applied to the VES-13-negative patients, the sensitivity and NPV improved to 90% and 88%, respectively. Conclusions: The 2-step approach exhibited better screening performance for frailty among patients with cancer than existing methods. Large prospective studies are required in the future to confirm this ability of the 2-step approach.

    DOI: 10.6004/jnccn.2015.0180

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  83. Screening Performance for Frailty Among Older Patients With Cancer: A Cross-Sectional Observational Study of Two Approaches 査読有り

    Toru Okuyama, Koji Sugano, Shinsuke Iida, Takashi Ishida, Shigeru Kusumoto, Tatsuo Akechi

    JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK   13 巻 ( 12 ) 頁: 1525 - 1531   2015年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:HARBORSIDE PRESS  

    Objectives: To investigate the screening performance for frailty of the Vulnerable Elders Survey-13 (VES-13) and the 2-step approach consisting of the VES-13 plus the anhedonia (loss of interest or pleasure) item from Patient Health Questionnaire-9 (PHQ-9) among older patients with newly diagnosed cancer. Methods: This study involved 106 consecutive inpatients aged 65 years or older, newly diagnosed with malignant lymphoma or multiple myeloma, just before chemotherapy initiation. The participants were administered the VES-13, and also underwent a comprehensive geriatric assessment (CGA), including for depression and 6 other geriatric conditions, using validated measures, just before initiation of chemotherapy. We defined frailty as the presence of 2 or more geriatric conditions as determined by the CGA. Receiver operating characteristic analysis was performed. The 2-step screening approach was examined by post hoc analysis. Results: The average age of the subjects was 74 years. Among the 106 subjects, 50% met the criteria for frailty. Using a cutoff score of 2 to 3 on the VES-13, a sensitivity and negative predictive value (NPV) of 72% of the screening tool was obtained for the condition of frailty. When the second step of the screening, consisting of the VES-13 plus anhedonia, was applied to the VES-13 negative patients, the sensitivity and NPV improved to 90% and 88%, respectively. Conclusions: The 2-step approach exhibited better screening performance for frailty among patients with cancer than existing methods. Large prospective studies are required in the future to confirm this ability of the 2-step approach.

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    PubMed

  84. [Prognostic significance of tryptophan catabolism in adult T-cell leukemia/lymphoma]. 査読有り

    Masaki A, Ishida T, Maeda Y, Suzuki S, Ito A, Takino H, Totani H, Yoshida T, Kinoshita S, Ogura H, Narita T, Ri M, Kusumoto S, Inagaki A, Komatsu H, Niimi A, Ueda R, Utsunomiya A, Inagaki H, Iida S

    [Rinsho ketsueki] The Japanese journal of clinical hematology   56 巻 ( 11 ) 頁: 2295 - 304   2015年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:[Rinshō ketsueki] The Japanese journal of clinical hematology  

    PURPOSE: Indoleamine 2,3-dioxygenase 1 (IDO1: IDO) is an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway, and is an important micro-environmental factor suppressing antitumor immune responses. We investigated the prognostic significance of Trp catabolism in adult T-cell leukemia/lymphoma (ATL).

    DOI: 10.11406/rinketsu.56.2295

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  85. ATLに対するモガムリズマブ治療 MIMOGA study 中間解析 査読有り

    石田 高司, 崔 日承, 宇都宮 與, 今泉 芳孝, 野坂 生郷, 佐分利 能生, 城 達郎, 石塚 賢治, 谷口 広明, 日高 道弘, 伊藤 旭, 楠本 茂, 上田 龍三

    日本癌学会総会記事   74回 巻   頁: E - 1229   2015年10月

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    記述言語:英語   出版者・発行元:日本癌学会  

  86. Phase Ia Study of FoxP3+ CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients. 査読有り

    Kurose K, Ohue Y, Wada H, Iida S, Ishida T, Kojima T, Doi T, Suzuki S, Isobe M, Funakoshi T, Kakimi K, Nishikawa H, Udono H, Oka M, Ueda R, Nakayama E

    Clinical cancer research : an official journal of the American Association for Cancer Research   21 巻 ( 19 ) 頁: 4327 - 4336   2015年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Clinical Cancer Research  

    Purpose: FoxP3+ Tregs inhibit immune responses against tumors. KW-0761 is a humanized anti-human CCR4 monoclonal antibody (mAb) that has antibody-dependent cellular cytotoxicity activity. Depletion of CCR4-expressing FoxP3+ CD4 Tregs by KW-0761 infusion was investigated in solid cancer patients. Experimental Design: We conducted a phase Ia clinical trial of KW-0761 infusion in 7 lung and 3 esophageal cancer patients. Toxicity, clinical efficacy, changes in lymphocyte subpopulations, includingTregs,andinductionofimmune responseswereanalyzed. Results: The results showed that KW-0761 infusion in a dose range between0.1mg/kg and 1.0mg/kgwas safe andwell tolerated. Nodose-limiting toxicitywas observed. Four of 10 patients showed stable disease during treatment and were long survivors. The monitoring of FoxP3+ Tregs in the peripheral blood mononuclear cells during treatment indicated efficient depletion of those cells, even at the lowest dose of 0.1 mg/kg used. The reduction in Th 1 CD4 T cells and CD8 T cells was limited, whereas a significant reduction was observed with Th 2 and Th 17 CD4 T cells. Immune responses to cancer/testis (CT) antigens and an autoantibody response to thyroid peroxidase were observed in some patients. Conclusions: The findings showed Tregs depletion and the possible occurrence of an immune response following KW-0761 infusion. Combined use of KW-0761 to deplete FoxP3+ Tregs with other immunotherapies, such as cancer vaccines or checkpoint inhibitors, is a promising approach to augment immune responses.

    DOI: 10.1158/1078-0432.CCR-15-0357

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  87. A phase II study of bortezomib in patients with relapsed or refractory aggressive adult T-cell leukemia/lymphoma 査読有り

    Kenji Ishitsuka, Atae Utsunomiya, Hiroo Katsuya, Shogo Takeuchi, Yoshifusa Takatsuka, Michihiro Hidaka, Tatsunori Sakai, Makoto Yoshimitsu, Takashi Ishida, Kazuo Tamura

    Cancer Science   106 巻 ( 9 ) 頁: 1219 - 1223   2015年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blackwell Publishing Ltd  

    Adult T-cell leukemia/lymphoma (ATL) is a malignancy of peripheral T-lymphocytes with a poor prognosis. This multicenter, two-stage, single-arm, phase II study assessed the efficacy and safety of bortezomib in patients with relapsed/refractory ATL who received at least one regimen of chemotherapy. The primary endpoint was the best overall response rate (ORR), and secondary endpoints included safety, the best response by lesions, and progression-free survival (PFS). Fifteen patients were enrolled in the first stage of this study. One partial remission (PR) and five stable disease (SD) were observed as the best overall responses, and ORR was 6.7% (95% confidence interval (C.I.) 0.17-31.95%). Responses according to disease sites were one complete remission (CR) in peripheral blood, two PR in measurable targeted lesions, and two PR in skin lesions. Progression-free survival (PFS) was 38 (95% CI
    18-106) days. All patients developed ≥1 adverse events (AEs), and 80% of patients had ≥1 grade 3/4 AEs
    however, no new safety findings were obtained. Although these results fulfilled the planned settings to proceed to the second stage, the coordinating committee decided to terminate this study because single agent activity did not appear to be very promising for this cohort of patients.

    DOI: 10.1111/cas.12735

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    PubMed

  88. A phase II study of bortezomib in patients with relapsed or refractory aggressive adult T-cell leukemia/lymphoma

    Ishitsuka K., Utsunomiya A., Katsuya H., Takeuchi S., Takatsuka Y., Hidaka M., Sakai T., Yoshimitsu M., Ishida T., Tamura K.

    Cancer Science   106 巻 ( 9 ) 頁: 1219 - 1223   2015年9月

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    記述言語:日本語   出版者・発行元:Cancer Science  

    Adult T-cell leukemia/lymphoma (ATL) is a malignancy of peripheral T-lymphocytes with a poor prognosis. This multicenter, two-stage, single-arm, phase II study assessed the efficacy and safety of bortezomib in patients with relapsed/refractory ATL who received at least one regimen of chemotherapy. The primary endpoint was the best overall response rate (ORR), and secondary endpoints included safety, the best response by lesions, and progression-free survival (PFS). Fifteen patients were enrolled in the first stage of this study. One partial remission (PR) and five stable disease (SD) were observed as the best overall responses, and ORR was 6.7% (95% confidence interval (C.I.) 0.17-31.95%). Responses according to disease sites were one complete remission (CR) in peripheral blood, two PR in measurable targeted lesions, and two PR in skin lesions. Progression-free survival (PFS) was 38 (95% CI; 18-106) days. All patients developed ≥1 adverse events (AEs), and 80% of patients had ≥1 grade 3/4 AEs; however, no new safety findings were obtained. Although these results fulfilled the planned settings to proceed to the second stage, the coordinating committee decided to terminate this study because single agent activity did not appear to be very promising for this cohort of patients.

    DOI: 10.1111/cas.12735

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  89. A phase II study of bortezomib in patients with relapsed or refractory aggressive adult T-cell leukemia/lymphoma 査読有り

    Kenji Ishitsuka, Atae Utsunomiya, Hiroo Katsuya, Shogo Takeuchi, Yoshifusa Takatsuka, Michihiro Hidaka, Tatsunori Sakai, Makoto Yoshimitsu, Takashi Ishida, Kazuo Tamura

    CANCER SCIENCE   106 巻 ( 9 ) 頁: 1219 - 1223   2015年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Adult T-cell leukemia/lymphoma (ATL) is a malignancy of peripheral T-lymphocytes with a poor prognosis. This multicenter, two-stage, single-arm, phase II study assessed the efficacy and safety of bortezomib in patients with relapsed/refractory ATL who received at least one regimen of chemotherapy. The primary endpoint was the best overall response rate (ORR), and secondary endpoints included safety, the best response by lesions, and progression-free survival (PFS). Fifteen patients were enrolled in the first stage of this study. One partial remission (PR) and five stable disease (SD) were observed as the best overall responses, and ORR was 6.7% (95% confidence interval (C.I.) 0.17-31.95%). Responses according to disease sites were one complete remission (CR) in peripheral blood, two PR in measurable targeted lesions, and two PR in skin lesions. Progression-free survival (PFS) was 38 (95% CI; 18-106) days. All patients developed &gt;= 1 adverse events (AEs), and 80% of patients had &gt;= 1 grade 3/4 AEs; however, no new safety findings were obtained. Although these results fulfilled the planned settings to proceed to the second stage, the coordinating committee decided to terminate this study because single agent activity did not appear to be very promising for this cohort of patients.

    DOI: 10.1111/cas.12735

    Web of Science

  90. A phase II study of bortezomib in patients with relapsed or refractory aggressive adult T-cell leukemia/lymphoma.

    Ishitsuka K, Utsunomiya A, Katsuya H, Takeuchi S, Takatsuka Y, Hidaka M, Sakai T, Yoshimitsu M, Ishida T, Tamura K

    Cancer science   106 巻 ( 9 ) 頁: 1219 - 23   2015年9月

     詳細を見る

    記述言語:英語  

    DOI: 10.1111/cas.12735

    PubMed

  91. Medical decision-making incapacity among newly diagnosed older patients with hematological malignancy receiving first line chemotherapy: A cross-sectional study of patients and physicians

    Sugano K., Okuyama T., Iida S., Komatsu H., Ishida T., Kusumoto S., Uchida M., Nakaguchi T., Kubota Y., Ito Y., Takahashi K., Akechi T.

    PLoS ONE   10 巻 ( 8 )   2015年8月

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    記述言語:日本語   出版者・発行元:PLoS ONE  

    Background Decision-making capacity to provide informed consent regarding treatment is essential among cancer patients. The purpose of this study was to identify the frequency of decisionmaking incapacity among newly diagnosed older patients with hematological malignancy receiving first-line chemotherapy, to examine factors associated with incapacity and assess physicians' perceptions of patients' decision-making incapacity. Methods Consecutive patients aged 65 years or over with a primary diagnosis of malignant lymphoma or multiple myeloma were recruited. Decision-making capacity was assessed using the Structured Interview for Competency and Incompetency Assessment Testing and Ranking Inventory-Revised (SICIATRI-R). Cognitive impairment, depressive condition and other possible associated factors were also evaluated. Results Among 139 eligible patients registered for this study, 114 completed the survey. Of these, 28 (25%, 95%confidence interval [CI]: 17%-32%) were judged as having some extent of decision-making incompetency according to SICIATRI-R. Higher levels of cognitive impairment and increasing age were significantly associated with decision-making incapacity. Physicians experienced difficulty performing competency assessment (Cohen's kappa-0.54). Conclusions Decision-making incapacity was found to be a common and under-recognized problem in older patients with cancer. Age and assessment of cognitive impairment may provide the opportunity to find patients that are at a high risk of showing decision-making incapacity. Copyright:

    DOI: 10.1371/journal.pone.0136163

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  92. Medical Decision-Making Incapacity among Newly Diagnosed Older Patients with Hematological Malignancy Receiving First Line Chemotherapy: A Cross-Sectional Study of Patients and Physicians 査読有り

    Koji Sugano, Toru Okuyama, Shinsuke Iida, Hirokazu Komatsu, Takashi Ishida, Shigeru Kusumoto, Megumi Uchida, Tomohiro Nakaguchi, Yosuke Kubota, Yoshinori Ito, Kazuhisa Takahashi, Tatsuo Akechi

    PLOS ONE   10 巻 ( 8 ) 頁: e0136163   2015年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Background
    Decision-making capacity to provide informed consent regarding treatment is essential among cancer patients. The purpose of this study was to identify the frequency of decision-making incapacity among newly diagnosed older patients with hematological malignancy receiving first-line chemotherapy, to examine factors associated with incapacity and assess physicians' perceptions of patients' decision-making incapacity.
    Methods
    Consecutive patients aged 65 years or over with a primary diagnosis of malignant lymphoma or multiple myeloma were recruited. Decision-making capacity was assessed using the Structured Interview for Competency and Incompetency Assessment Testing and Ranking Inventory-Revised (SICIATRI-R). Cognitive impairment, depressive condition and other possible associated factors were also evaluated.
    Results
    Among 139 eligible patients registered for this study, 114 completed the survey. Of these, 28 (25%, 95% confidence interval [CI]: 17%-32%) were judged as having some extent of decision- making incompetency according to SICIATRI-R. Higher levels of cognitive impairment and increasing age were significantly associated with decision-making incapacity. Physicians experienced difficulty performing competency assessment (Cohen's kappa -0.54).
    Conclusions
    Decision-making incapacity was found to be a common and under-recognized problem in older patients with cancer. Age and assessment of cognitive impairment may provide the opportunity to find patients that are at a high risk of showing decision-making incapacity.

    DOI: 10.1371/journal.pone.0136163

    Web of Science

    PubMed

  93. Medical Decision-Making Incapacity among Newly Diagnosed Older Patients with Hematological Malignancy Receiving First Line Chemotherapy: A Cross-Sectional Study of Patients and Physicians 査読有り

    Koji Sugano, Toru Okuyama, Shinsuke Iida, Hirokazu Komatsu, Takashi Ishida, Shigeru Kusumoto, Megumi Uchida, Tomohiro Nakaguchi, Yosuke Kubota, Yoshinori Ito, Kazuhisa Takahashi, Tatsuo Akechi

    PLOS ONE   10 巻 ( 8 )   2015年8月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Background
    Decision-making capacity to provide informed consent regarding treatment is essential among cancer patients. The purpose of this study was to identify the frequency of decision-making incapacity among newly diagnosed older patients with hematological malignancy receiving first-line chemotherapy, to examine factors associated with incapacity and assess physicians' perceptions of patients' decision-making incapacity.
    Methods
    Consecutive patients aged 65 years or over with a primary diagnosis of malignant lymphoma or multiple myeloma were recruited. Decision-making capacity was assessed using the Structured Interview for Competency and Incompetency Assessment Testing and Ranking Inventory-Revised (SICIATRI-R). Cognitive impairment, depressive condition and other possible associated factors were also evaluated.
    Results
    Among 139 eligible patients registered for this study, 114 completed the survey. Of these, 28 (25%, 95% confidence interval [CI]: 17%-32%) were judged as having some extent of decision- making incompetency according to SICIATRI-R. Higher levels of cognitive impairment and increasing age were significantly associated with decision-making incapacity. Physicians experienced difficulty performing competency assessment (Cohen's kappa -0.54).
    Conclusions
    Decision-making incapacity was found to be a common and under-recognized problem in older patients with cancer. Age and assessment of cognitive impairment may provide the opportunity to find patients that are at a high risk of showing decision-making incapacity.

    DOI: 10.1371/journal.pone.0136163

    Web of Science

  94. Randomized phase II trial comparing amrubicin with re-challenge of platinum doublet in patients with sensitive-relapsed small-cell lung cancer: North Japan Lung Cancer Study Group trial 0702.

    Inoue A, Sugawara S, Maemondo M, Mori Y, Oizumi S, Harada M, Taima K, Morikawa N, Ishida T, Kinoshita I, Watanabe H, Suzuki T, Nakagawa T, Saito R, Nukiwa T

    Lung cancer (Amsterdam, Netherlands)   89 巻 ( 1 ) 頁: 61 - 5   2015年7月

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    記述言語:英語  

    DOI: 10.1016/j.lungcan.2015.04.012

    PubMed

  95. Transplant-related mortality following allogeneic hematopoietic stem cell transplantation using fludarabine/busulfan-based reduced-intensity conditioning - A retrospective analysis in a single institution 査読有り

    Takashi Yoshida, Shigeru Kusumoto, Arisa Masuda, Haruhito Totani, Tomoko Narita, Ayako Masaki, Asahi Ito, Masaki Ri, Takashi Ishida, Hirokazu Komatsu, Shinsuke Iida

    Japanese Journal of Cancer and Chemotherapy   42 巻 ( 6 ) 頁: 719 - 724   2015年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

    Reduced-intensity conditioning (RIC) has been shown to facilitate allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with comorbidities and the elderly. However, there are some concerns about transplant-related mortality (TRM). We retrospectively analyzed 37 consecutive patients who received allo-HSCT using RIC from January 2005 to December 2012 in our hospital. All patients received fludarabine (FLU), 180 mg/m2, and intravenous busulfan (BU), 6.4 mg/kg (or oral BU 8 mg/kg), with or without TBI (2 or 4 Gy). Cyclosporine or tacrolimus alone, or in combination with shortterm methotrexate therapy was used for GVHD prophylaxis. Donor sources included related peripheral blood donors (n=4), and related (n=8) and unrelated (n=25) bone marrow donors. The underlying diseases were various, and 27 patients were considered to be at standard risk. Although one patient died of early disease progression, engraftment was achieved for the others. With a median follow-up of 28.5 months, the estimated 1-year and 5-year TRMs were 13% and 20%, respectively. Five patients died of transplant-related complications, which consisted of 2 cases of acute GVHD and 1 case each of interstitial pneumonitis, bronchiolitis obliterans, and infectious pneumonia. In conclusion, FLU/BU-based RIC is tolerable, but further optimization is needed to prevent transplant-related complications.

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  96. Transplant-related mortality following allogeneic hematopoietic stem cell transplantation using fludarabine/busulfan-based reduced-intensity conditioning - A retrospective analysis in a single institution

    Yoshida T., Kusumoto S., Masuda A., Totani H., Narita T., Masaki A., Ito A., Ri M., Ishida T., Komatsu H., Iida S.

    Japanese Journal of Cancer and Chemotherapy   42 巻 ( 6 ) 頁: 719 - 724   2015年6月

     詳細を見る

    記述言語:日本語   出版者・発行元:Japanese Journal of Cancer and Chemotherapy  

    Reduced-intensity conditioning (RIC) has been shown to facilitate allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with comorbidities and the elderly. However, there are some concerns about transplant-related mortality (TRM). We retrospectively analyzed 37 consecutive patients who received allo-HSCT using RIC from January 2005 to December 2012 in our hospital. All patients received fludarabine (FLU), 180 mg/m2, and intravenous busulfan (BU), 6.4 mg/kg (or oral BU 8 mg/kg), with or without TBI (2 or 4 Gy). Cyclosporine or tacrolimus alone, or in combination with shortterm methotrexate therapy was used for GVHD prophylaxis. Donor sources included related peripheral blood donors (n=4), and related (n=8) and unrelated (n=25) bone marrow donors. The underlying diseases were various, and 27 patients were considered to be at standard risk. Although one patient died of early disease progression, engraftment was achieved for the others. With a median follow-up of 28.5 months, the estimated 1-year and 5-year TRMs were 13% and 20%, respectively. Five patients died of transplant-related complications, which consisted of 2 cases of acute GVHD and 1 case each of interstitial pneumonitis, bronchiolitis obliterans, and infectious pneumonia. In conclusion, FLU/BU-based RIC is tolerable, but further optimization is needed to prevent transplant-related complications.

    Scopus

  97. [Transplant-Related Mortality Following Allogeneic Hematopoietic Stem Cell Transplantation Using Fludarabine/Busulfan-Based Reduced-Intensity Conditioning - A Retrospective Analysis in a Single Institution].

    Yoshida T, Kusumoto S, Masuda A, Totani H, Narita T, Masaki A, Ito A, Ri M, Ishida T, Komatsu H, Iida S

    Gan to kagaku ryoho. Cancer & chemotherapy   42 巻 ( 6 ) 頁: 719 - 24   2015年6月

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    記述言語:日本語  

    PubMed

  98. Prognostic Significance of Tryptophan Catabolism in Adult T-cell Leukemia/Lymphoma. 査読有り

    Masaki A, Ishida T, Maeda Y, Suzuki S, Ito A, Takino H, Ogura H, Totani H, Yoshida T, Kinoshita S, Narita T, Ri M, Kusumoto S, Inagaki A, Komatsu H, Niimi A, Ueda R, Utsunomiya A, Inagaki H, Iida S

    Clinical cancer research : an official journal of the American Association for Cancer Research   21 巻 ( 12 ) 頁: 2830 - 2839   2015年6月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Clinical Cancer Research  

    Purpose: Indoleamine 2,3-dioxygenase 1 (IDO1: IDO), an enzyme catabolizing tryptophan (Trp) into the kynurenine (Kyn) pathway, is increasingly being recognized as an important microenvironmental factor suppressing antitumor immune responses. The purpose of the present study was to determine the prognostic significance of Trp catabolism in adult T-cell leukemia/lymphoma (ATL). Experimental Design: We quantified serum Trp and Kyn in 96 ATL patients, 38 human T-cell lymphotropic virus type-1 asymptomatic carriers (HTLV-1 ACs), and 40 healthy adult volunteer controls. The relationships between various clinical parameters including overall survival were analyzed. IDO expression was evaluated in the affected lymph nodes of ATL patients. Results: Serum Kyn concentrations and Kyn/Trp ratios were significantly higher in HTLV-1 ACs than healthy controls. Both increased significantly with progression from HTLV-1 AC to ATL. However, there were no significant differences in the serum Trp concentrations between ATL patients, HTLV-1 ACs, and controls. IDO was possibly produced by ATL and/or cells of the microenvironment. Multivariate analyses demonstrated that a high serum Kyn/Trp ratio and high Kyn level, but not a high Trp level, were significantly independent detrimental prognostic factors in ATL, as well as in that subset of patients with aggressive variant ATL. Conclusions: Quantification of serum Kyn and Trp is useful for predicting prognosis of an individual ATL patient. Furthermore, ATL, especially in patients with a high serum Kyn/ Trp ratio, is an appropriate disease for testing novel cancer immunotherapies targeting IDO.

    DOI: 10.1158/1078-0432.CCR-14-2275

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    PubMed

  99. [Development of mogamulizumab and establishment of an optimal therapy based on genomic biomarkers: from the academic viewpoint]. 査読有り

    Iida S, Ishida T, Ueda R

    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan   135 巻 ( 5 ) 頁: 663 - 669   2015年5月

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    記述言語:日本語   出版者・発行元:Yakugaku Zasshi  

    Mogamulizumab (Moga; KW 0761) is a defucosylated humanized anti-CC chemokine receptor 4 (CCR4) antibody engineered to exert potent antibody-dependent cellular cytotoxicity (ADCC). A collaborative investigation with industry in preclinical studies has demonstrated in vitro and in vivo e‹cacy via ADCC for adult T-cell leukemia/lym- phoma (ATLL) and CCR4-positive peripheral T-cell lymphoma (PTCL). In a phase I study, once-weekly administra- tion of mogamulizumab (0.01-1.0 mg/kg) for 4 weeks was well tolerated. In a phase II study of once-weekly mogamulizumab (1.0 mg/kg) for 8 weeks in relapsed/refractory ATLL patients, an overall response rate of 50% in- cluding 30% complete response rate with a median progression-free survival of 5.2 months was observed. The drug was subsequently approved by Pharmaceuticals and Medical Devices Agency(PMDA) in March 2012. Because CCR4 is abundantly expressed on the surface of eŠector regulatory T cells, a phase I study is being conducted to enhance an- titumor immune response in patients with solid tumors. However, approximately 60% of patients receiving mogamulizumab experience skin eruption with 19% showing grade 3 rash. Postmarketing surveillance of mogamulizumab revealed a 3-4% incidence rate of skin-related serious adverse events (SAEs) such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Therefore we initiated a search for predictive genomic biomar- kers in the blood of patients with ATLL or solid tumors prior to treatment with mogamulizumab for not only e‹cacy but also immune-related SAEs. We believe the results of this study may lead to safer and more e‹cient use of this agent in the near future.

    DOI: 10.1248/yakushi.14-00230-3

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  100. ALアミロイドーシス診断における口唇唾液腺生検の有用性 後方視的解析

    鈴木 智貴, 楠本 茂, 山下 太郎, 増田 有彩, 木下 史緒理, 吉田 嵩, 高見 芙美子[森], 滝野 寿, 伊藤 旭, 李 政樹, 石田 高司, 小松 弘和, 植田 光晴, 安東 由喜雄, 稲垣 宏, 飯田 真介

    International Journal of Myeloma   5 巻 ( 2 ) 頁: 85 - 85   2015年5月

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    記述言語:日本語   出版者・発行元:日本骨髄腫学会  

  101. Quantitative evaluation of annular bright-field phase images in STEM

    Ishida Takafumi, Kawasaki Tadahiro, Tanji Takayoshi, Ikuta Takashi

    MICROSCOPY   64 巻 ( 2 ) 頁: 121 - 128   2015年4月

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    記述言語:日本語   出版者・発行元:Microscopy  

    A phase reconstruction method based on multiple scanning transmission electron microscope (STEM) images was evaluated quantitatively using image simulations. The simulation results indicated that the phase shift caused by a single atom was proportional to the 0.6th power of the atomic number Z. For a thin SrTiO3 [001] crystal, the reconstructed phase at each atomic column increased according to the specimen thickness. The STEM phase images can quantify the oxygen vacancy concentration if the thickness is less than several nanometers.

    DOI: 10.1093/jmicro/dfu113

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  102. Reactivation of hepatitis B virus (HBV) infection in adult T-cell leukemia-lymphoma patients with resolved HBV infection following systemic chemotherapy. 査読有り

    Totani H, Kusumoto S, Ishida T, Masuda A, Yoshida T, Ito A, Ri M, Komatsu H, Murakami S, Mizokami M, Ueda R, Niimi A, Inagaki H, Tanaka Y, Iida S

    International journal of hematology   101 巻 ( 4 ) 頁: 398 - 404   2015年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Hematology  

    Reactivation of hepatitis B virus (HBV) infection may occur in adult T-cell leukemia–lymphoma (ATL) patients with resolved HBV infection who receive monotherapy with the anti-CC chemokine receptor 4 monoclonal antibody, mogamulizumab. However, there is little evidence regarding the incidence and characteristics of HBV reactivation in ATL patients receiving systemic chemotherapy, including the use of this antibody. We conducted a retrospective study for 24 ATL patients with resolved HBV infection underwent regular HBV DNA monitoring to assess HBV reactivation in Nagoya City University Hospital between January 2005 and June 2013. With median HBV DNA follow-up of 238 days (range 57–1420), HBV reactivation (defined as the detection of HBV DNA) was observed in three (12.5 %) of 24 patients with resolved HBV infection. No hepatitis due to HBV reactivation occurred in those patients who were diagnosed with HBV DNA levels below 2.1 log copies/mL and who received antiviral drugs. Mogamulizumab was administered prior to HBV reactivation in two of three HBV-reactivated patients. In the mogamulizumab era, further well-designed prospective studies are warranted to estimate the incidence of HBV reactivation and to establish regular HBV DNA monitoring-guided preemptive antiviral therapy for such patients.

    DOI: 10.1007/s12185-015-1750-z

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  103. [Case Report; An intestinal extranodal NK/T cell lymphoma mimicking Crohn's disease].

    Kominato S, Kusumoto S, Masuda A, Ishida T, Komatsu H, Mizoshita T, Joh T, Niimi A, Inagaki H, Iida S

    Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine   104 巻 ( 2 ) 頁: 298 - 301   2015年2月

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    記述言語:日本語   出版者・発行元:一般社団法人 日本内科学会  

    44歳,男性.くり返す下痢,腹痛,嘔吐,発熱あり,ダブルバルーン内視鏡(double balloon endoscopy:DBE)で小腸型Crohn病と診断された.治療抵抗性を示し,CTで腹腔内リンパ節腫大,肝腫大を指摘.FDG-PETで腹腔内リンパ節と胃噴門部に異常集積を認め,胃検体の免疫染色およびEBV(Epstein-Barr virus)モノクロナリティにて,腸管節外性NK/T細胞リンパ腫と診断した.後方視的にDBEの小腸検体で同様の病理所見を認め,化学療法にて症状と検査所見は著明に改善した.

    DOI: 10.2169/naika.104.298

    PubMed

  104. [Case Report; An intestinal extranodal NK/T cell lymphoma mimicking Crohn's disease]. 査読有り

    Kominato S, Kusumoto S, Masuda A, Ishida T, Komatsu H, Mizoshita T, Joh T, Niimi A, Inagaki H, Iida S

    Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine   104 巻 ( 2 ) 頁: 298 - 301   2015年2月

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  105. CD30-positive primary bone marrow lymphoma mimicking Hodgkin lymphoma. 査読有り

    Suzuki T, Kusumoto S, Masaki A, Ishida T, Inagaki H, Iida S, Mori F

    International journal of hematology   101 巻 ( 2 ) 頁: 109 - 111   2015年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Hematology  

    DOI: 10.1007/s12185-014-1714-8

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  106. Risk Stratification of Outcomes Among Patients with Adult T-Cell Leukemia/Lymphoma Receiving Allogeneic Hematopoietic Cell Transplantation: A Retrospective Analysis of the JSHCT An Working Group

    Yoshimitsu Makoto, Tanosaki Ryuji, Kato Koji, Ishida Takashi, Choi Ilseung, Fukuda Takahiro, Takatsuka Yoshifusa, Eto Tetsuya, Uchida Naoyuki, Moriuchi Yukiyoshi, Nagamura-Inoue Tokiko, Mori Shin-Ichiro, Sakamaki Hisashi, Atsuta Yoshiko, Utsunomiya Atae

    BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION   21 巻 ( 2 ) 頁: S89 - S90   2015年2月

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    記述言語:日本語  

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  107. Progress in clinical use of CC Chemokine receptor 4 antibody for regulatory T cell suppression 査読有り

    Suzuki S., Ishida T., Yoshikawa K., Ueda R.

    Inflammation and Immunity in Cancer     頁: 207 - 227   2015年1月

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    記述言語:英語   掲載種別:論文集(書籍)内論文   出版者・発行元:Inflammation and Immunity in Cancer  

    Recent clinical research advances in tumor immunity provide hope for the development of a novel tumor immunotherapy. Many clinical studies of cancer vaccines over the past 10 years have shown the augmentation of tumor immunity in some patients, although the clinical effects have been low. In addition, it was reported that blocking regulatory molecules involved in the immune checkpoint is important for immune activation in both in vitro and in vivo studies. In particular, studies using blocking antibodies to cytotoxic T lymphocyte-associated antigen (CTLA)-4, programmed cell death protein (PD)-1, or PD-1 ligand 1 (PD-L1) observed significant clinical effects including complete remission, suggesting that regulation of regulatory signals in the immune checkpoint is a new direction for the development of new drugs based on tumor immunity. As regulatory T cells (Tregs) also plays a key role in immune regulation, just as the regulatory molecules in the immune checkpoint become targets for the development of novel tumor immunotherapy, they may also become a target for development. Several reports have suggested that Tregs that infiltrate tumor sites as well as regulatory signals for immune checkpoints can inhibit tumor immunity, which is one explanation why treatment by cancer vaccine is limited. CC chemokine receptor 4 (CCR4) is selectively expressed on effector Tregs, and humanized monoclonal antibodies to CCR4 have been developed as a drug, ‘mogamulizumab’, to treat adult T cell leukemia/lymphoma (ATLL). Mogamulizumab depletes both ATLL cells and normal Tregs, resulting in the recovery of immune function in ATLL patients. Mogamulizumab is now expected to be accepted for use as a novel immuno-activator for tumor therapy by depletion of Tregs and is undergoing phase Ia/Ib studies for treatment of solid tumors in the lung, esophagus, intestine, ovary, and melanoma.

    DOI: 10.1007/978-4-431-55327-4_17

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  108. Medical Decision-Making Incapacity among Newly Diagnosed Older Patients with Hematological Malignancy Receiving First Line Chemotherapy: A Cross-Sectional Study of Patients and Physicians.

    Sugano K, Okuyama T, Iida S, Komatsu H, Ishida T, Kusumoto S, Uchida M, Nakaguchi T, Kubota Y, Ito Y, Takahashi K, Akechi T

    PloS one   10 巻 ( 8 ) 頁: e0136163   2015年

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    記述言語:英語  

    DOI: 10.1371/journal.pone.0136163

    PubMed

  109. Quantitative Reconstruction of Sulfur Deposition Using a Mixing Model Based on Sulfur Isotope Ratios in Tree Rings

    Ishida Takuya, Tayasu Ichiro, Takenaka Chisato

    JOURNAL OF ENVIRONMENTAL QUALITY   44 巻 ( 6 ) 頁: 1800 - 1808   2015年

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    記述言語:日本語  

    DOI: 10.2134/jeq2014.11.0506

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  110. An integrated manual for hematologists and dermatologists to access the guidelines for the management of adult T-cell leukemia-lymphoma (2014).

    Ishida T, Itoh A, Tokura Y, Tanaka J, Uike N, Tobinai K, Tsukasaki K

    [Rinsho ketsueki] The Japanese journal of clinical hematology   55 巻 ( 11 ) 頁: 2257 - 61   2014年11月

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    記述言語:日本語  

    PubMed

  111. Prognostic impact of microRNA-145 down-regulation in adult T-cell leukemia/lymphoma 査読有り

    Hongjing Xia, Seiji Yamada, Mineyoshi Aoyama, Fumihiko Sato, Ayako Masaki, Yan Ge, Masaki Ri, Takashi Ishida, Ryuzo Ueda, Atae Utsunomiya, Kiyofumi Asai, Hiroshi Inagaki

    HUMAN PATHOLOGY   45 巻 ( 6 ) 頁: 1192 - 1198   2014年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:W B SAUNDERS CO-ELSEVIER INC  

    Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive tumor caused by human T-cell leukemia virus type 1. MicroRNAs (miRNAs) are closely involved in the development and progression of various tumors. Here we investigated the dysregulation of miRNAs in ATL and its clinical significance. Studies using miRNA arrays and subsequent real-time reverse transcription polymerase chain reaction showed that, in the 9 ATL cell lines examined, 1 miRNA was consistently up-regulated, whereas another 3 were consistently down-regulated, compared with normal CD4-positive lymphocytes. Next, we analyzed the prognostic impact of these 4 miRNAs in patients with aggressive-type AIL (n = 40). Of the 4 dysregulated miRNAs selected, 3 (miR-130b higher expression, miR-145 lower expression, and miR-223 lower expression) were significantly associated with a worsened overall patient survival. We found that expressions of these 3 miRNAs were correlated with each other. To clarify which of the 3 had the most significant impact on overall survival, we performed a multivariate prognostic analysis that included these 3 miRNAs, and only miR-145 lower expression was selected as an independent risk factor (P = .0005). When overexpressed in an AIL cell line in vitro, miR-145 specifically inhibited tumor cell growth. In conclusion, our study suggests that miR-145 down-regulation provides a growth advantage in ATL and is highly associated with a worsened prognosis for patients with ALT. Hence, miR-145 may be a useful prognostic marker and a potential therapeutic target for ATL. (C) 2014 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.humpath.2014.01.017

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  112. Prognostic impact of microRNA-145 down-regulation in adult T-cell leukemia/lymphoma.

    Xia H, Yamada S, Aoyama M, Sato F, Masaki A, Ge Y, Ri M, Ishida T, Ueda R, Utsunomiya A, Asai K, Inagaki H

    Human pathology   45 巻 ( 6 ) 頁: 1192 - 8   2014年6月

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    記述言語:英語  

    DOI: 10.1016/j.humpath.2014.01.017

    PubMed

  113. Prognostic impact of microRNA-145 down-regulation in adult T-cell leukemia/lymphoma

    Xia H., Yamada S., Aoyama M., Sato F., Masaki A., Ge Y., Ri M., Ishida T., Ueda R., Utsunomiya A., Asai K., Inagaki H.

    Human Pathology   45 巻 ( 6 ) 頁: 1192 - 1198   2014年6月

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    記述言語:日本語   出版者・発行元:Human Pathology  

    Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive tumor caused by human T-cell leukemia virus type 1. MicroRNAs (miRNAs) are closely involved in the development and progression of various tumors. Here we investigated the dysregulation of miRNAs in ATL and its clinical significance. Studies using miRNA arrays and subsequent real-time reverse transcription polymerase chain reaction showed that, in the 9 ATL cell lines examined, 1 miRNA was consistently up-regulated, whereas another 3 were consistently down-regulated, compared with normal CD4-positive lymphocytes. Next, we analyzed the prognostic impact of these 4 miRNAs in patients with aggressive-type ATL (n = 40). Of the 4 dysregulated miRNAs selected, 3 (miR-130b higher expression, miR-145 lower expression, and miR-223 lower expression) were significantly associated with a worsened overall patient survival. We found that expressions of these 3 miRNAs were correlated with each other. To clarify which of the 3 had the most significant impact on overall survival, we performed a multivariate prognostic analysis that included these 3 miRNAs, and only miR-145 lower expression was selected as an independent risk factor (P =.0005). When overexpressed in an ATL cell line in vitro, miR-145 specifically inhibited tumor cell growth. In conclusion, our study suggests that miR-145 down-regulation provides a growth advantage in ATL and is highly associated with a worsened prognosis for patients with ALT. Hence, miR-145 may be a useful prognostic marker and a potential therapeutic target for ATL. © 2014 Elsevier Inc.

    DOI: 10.1016/j.humpath.2014.01.017

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  114. Prognostic impact of microRNA-145 down-regulation in adult T-cell leukemia/lymphoma 査読有り

    Hongjing Xia, Seiji Yamada, Mineyoshi Aoyama, Fumihiko Sato, Ayako Masaki, Yan Ge, Masaki Ri, Takashi Ishida, Ryuzo Ueda, Atae Utsunomiya, Kiyofumi Asai, Hiroshi Inagaki

    HUMAN PATHOLOGY   45 巻 ( 6 ) 頁: 1192 - 1198   2014年6月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:W B SAUNDERS CO-ELSEVIER INC  

    Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive tumor caused by human T-cell leukemia virus type 1. MicroRNAs (miRNAs) are closely involved in the development and progression of various tumors. Here we investigated the dysregulation of miRNAs in ATL and its clinical significance. Studies using miRNA arrays and subsequent real-time reverse transcription polymerase chain reaction showed that, in the 9 ATL cell lines examined, 1 miRNA was consistently up-regulated, whereas another 3 were consistently down-regulated, compared with normal CD4-positive lymphocytes. Next, we analyzed the prognostic impact of these 4 miRNAs in patients with aggressive-type AIL (n = 40). Of the 4 dysregulated miRNAs selected, 3 (miR-130b higher expression, miR-145 lower expression, and miR-223 lower expression) were significantly associated with a worsened overall patient survival. We found that expressions of these 3 miRNAs were correlated with each other. To clarify which of the 3 had the most significant impact on overall survival, we performed a multivariate prognostic analysis that included these 3 miRNAs, and only miR-145 lower expression was selected as an independent risk factor (P = .0005). When overexpressed in an AIL cell line in vitro, miR-145 specifically inhibited tumor cell growth. In conclusion, our study suggests that miR-145 down-regulation provides a growth advantage in ATL and is highly associated with a worsened prognosis for patients with ALT. Hence, miR-145 may be a useful prognostic marker and a potential therapeutic target for ATL. (C) 2014 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.humpath.2014.01.017

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  115. Antitumor effects of bevacizumab in a microenvironment-dependent human adult T-cell leukemia/lymphoma mouse model. 査読有り

    Mori F, Ishida T, Ito A, Sato F, Masaki A, Narita T, Suzuki S, Yamada T, Takino H, Ri M, Kusumoto S, Komatsu H, Hishizawa M, Imada K, Takaori-Kondo A, Niimi A, Ueda R, Inagaki H, Iida S

    European journal of haematology   92 巻 ( 3 ) 頁: 219 - 228   2014年3月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:European Journal of Haematology  

    Objective: The objective of this study was to evaluate the therapeutic potential of bevacizumab with or without systemic chemotherapy for adult T-cell leukemia/lymphoma (ATL) and clarify the significance of angiogenesis for ATL pathogenesis. Methods: NOD/Shi-scid, IL-2Rγnull (NOG) mice were used as recipients of tumor cells from a patient with ATL, which engraft and proliferate in a microenvironment-dependent manner. The ATL cells could be serially transplanted in NOG mice, but could not be maintained in in vitro cultures. Results: Injection of bevacizumab alone significantly increased necrosis and decreased vascularization in the tumor tissue. Levels of human soluble interleukin two receptor in the serum (reflecting the ATL tumor burden) of bevacizumab-treated mice were significantly lower than in untreated mice. Although bevacizumab monotherapy showed these clear anti-angiogenesis effects, it did not prolong survival. In contrast, injection of bevacizumab together with cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) led to a significant prolongation of survival of the ATL mice relative to CHOP alone. Conclusions: This is the first report to evaluate the efficacy of bevacizumab for ATL in a tumor microenvironment-dependent model. Bevacizumab therapy combined with chemotherapy could be a valuable treatment strategy for that subgroup of ATL probably depending to a large extent on angiogenesis via vascular endothelial growth factor. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

    DOI: 10.1111/ejh.12231

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  116. Reactivation of hepatitis B virus in a patient with adult T-cell leukemia-lymphoma receiving the anti-CC chemokine receptor 4 antibody mogamulizumab. 査読有り

    Nakano N, Kusumoto S, Tanaka Y, Ishida T, Takeuchi S, Takatsuka Y, Akinaga S, Mizokami M, Ueda R, Utsunomiya A

    Hepatology research : the official journal of the Japan Society of Hepatology   44 巻 ( 3 ) 頁: 354 - 357   2014年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Hepatology Research  

    The introduction of molecularly targeted drugs has increased the risk of reactivation of hepatitis B virus (HBV), which is a potentially fatal complication following anticancer chemotherapy even in patients who have previously resolved their HBV infection. CC chemokine receptor 4 (CCR4) has been identified as a novel molecular target in antibody therapy for patients with adult T-cell leukemia-lymphoma (ATL) and peripheral T-cell lymphoma, and the humanized anti-CCR4 monoclonal antibody mogamulizumab has been developed. We reported HBV reactivation of an ATL patient with previously resolved HBV infection after mogamulizumab treatment in a dose-finding study for this antibody. Our retrospective analysis using preserved samples also revealed the detailed kinetics of HBV DNA levels before and just after HBV reactivation. © 2013 The Japan Society of Hepatology.

    DOI: 10.1111/hepr.12117

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  117. 血液内科医・皮膚科医のための統合ATL診療ガイドライン解説書2014

    石田 高司, 伊藤 旭, 戸倉 新樹, 田中 淳司, 鵜池 直邦, 飛内 賢正, 塚崎 邦弘

    臨床血液   55 巻 ( 11 ) 頁: 2257 - 2261   2014年

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    記述言語:日本語   出版者・発行元:The Japanese Society of Hematology  

    DOI: 10.11406/rinketsu.55.2257

    CiNii Books

    その他リンク: https://jlc.jst.go.jp/DN/JLC/20000648576?from=CiNii

  118. Global real-time quantitative reverse transcription-polymerase chain reaction detecting proto-oncogenes associated with 14q32 chromosomal translocation as a valuable marker for predicting survival in multiple myeloma 査読有り

    Atsushi Inagaki, Emi Tajima, Miyuki Uranishi, Haruhito Totani, Yu Asao, Hiroka Ogura, Ayako Masaki, Tatsuya Yoshida, Fumiko Mori, Asahi Ito, Hiroki Yano, Masaki Ri, Satoshi Kayukawa, Takae Kataoka, Shigeru Kusumoto, Takashi Ishida, Yoshihito Hayami, Ichiro Hanamura, Hirokazu Komatsu, Hiroshi Inagaki, Yasufumi Matsuda, Ryuzo Ueda, Shinsuke Iida

    LEUKEMIA RESEARCH   37 巻 ( 12 ) 頁: 1648 - 1655   2013年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    CCND1, FGFR3 and c-MAF mRNA expression of tumor samples from 123 multiple myeloma patients were analyzed by global RQJRT-PCR. CCNDI, FGFR3 and c-MAF were positive in 44(36%), 28(23%) and 16(13%) of patients, respectively. In 7 patients, both FGFR3 and c-MAF were positive. The expression of c-MAF was independent unfavorable prognostic factors for overall survival (OS). Autologous stem cell transplantation improved progression-free survival of CCND1-positive patients. Bortezomib, thalidomide or lenalidomide extended OS of FGFR3 and/or c-MAF-positive patients. Thus, CCNDI, FGFR3 and c-MAF mRNA expression can predict survival and is useful for planning stratified treatment strategies for myeloma patients. (C) 2013 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.leukres.2013.09.026

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  119. Global real-time quantitative reverse transcription-polymerase chain reaction detecting proto-oncogenes associated with 14q32 chromosomal translocation as a valuable marker for predicting survival in multiple myeloma 査読有り

    Atsushi Inagaki, Emi Tajima, Miyuki Uranishi, Haruhito Totani, Yu Asao, Hiroka Ogura, Ayako Masaki, Tatsuya Yoshida, Fumiko Mori, Asahi Ito, Hiroki Yano, Masaki Ri, Satoshi Kayukawa, Takae Kataoka, Shigeru Kusumoto, Takashi Ishida, Yoshihito Hayami, Ichiro Hanamura, Hirokazu Komatsu, Hiroshi Inagaki, Yasufumi Matsuda, Ryuzo Ueda, Shinsuke Iida

    LEUKEMIA RESEARCH   37 巻 ( 12 ) 頁: 1648 - 1655   2013年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    CCND1, FGFR3 and c-MAF mRNA expression of tumor samples from 123 multiple myeloma patients were analyzed by global RQJRT-PCR. CCNDI, FGFR3 and c-MAF were positive in 44(36%), 28(23%) and 16(13%) of patients, respectively. In 7 patients, both FGFR3 and c-MAF were positive. The expression of c-MAF was independent unfavorable prognostic factors for overall survival (OS). Autologous stem cell transplantation improved progression-free survival of CCND1-positive patients. Bortezomib, thalidomide or lenalidomide extended OS of FGFR3 and/or c-MAF-positive patients. Thus, CCNDI, FGFR3 and c-MAF mRNA expression can predict survival and is useful for planning stratified treatment strategies for myeloma patients. (C) 2013 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.leukres.2013.09.026

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  120. Global real-time quantitative reverse transcription-polymerase chain reaction detecting proto-oncogenes associated with 14q32 chromosomal translocation as a valuable marker for predicting survival in multiple myeloma

    Inagaki A., Tajima E., Uranishi M., Totani H., Asao Y., Ogura H., Masaki A., Yoshida T., Mori F., Ito A., Yano H., Ri M., Kayukawa S., Kataoka T., Kusumoto S., Ishida T., Hayami Y., Hanamura I., Komatsu H., Inagaki H., Matsuda Y., Ueda R., Iida S.

    Leukemia Research   37 巻 ( 12 ) 頁: 1648 - 1655   2013年12月

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    記述言語:日本語   出版者・発行元:Leukemia Research  

    CCND1, FGFR3 and c-MAF mRNA expression of tumor samples from 123 multiple myeloma patients were analyzed by global RQ/RT-PCR. CCND1, FGFR3 and c-MAF were positive in 44 (36%), 28 (23%) and 16 (13%) of patients, respectively. In 7 patients, both FGFR3 and c-MAF were positive. The expression of c-MAF was independent unfavorable prognostic factors for overall survival (OS). Autologous stem cell transplantation improved progression-free survival of CCND1-positive patients. Bortezomib, thalidomide or lenalidomide extended OS of FGFR3 and/or c-MAF-positive patients. Thus, CCND1, FGFR3 and c-MAF mRNA expression can predict survival and is useful for planning stratified treatment strategies for myeloma patients. © 2013 Elsevier Ltd.

    DOI: 10.1016/j.leukres.2013.09.026

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  121. Pulmonary fibrosis in dyskeratosis congenita with TINF2 gene mutation.

    Fukuhara A, Tanino Y, Ishii T, Inokoshi Y, Saito K, Fukuhara N, Sato S, Saito J, Ishida T, Yamaguchi H, Munakata M

    The European respiratory journal   42 巻 ( 6 ) 頁: 1757 - 9   2013年12月

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    記述言語:英語  

    DOI: 10.1183/09031936.00149113

    PubMed

  122. Impact of Graft-versus-Host Disease on Allogeneic Hematopoietic Cell Transplantation for Adult T Cell Leukemia-Lymphoma Focusing on Preconditioning Regimens: Nationwide Retrospective Study 査読有り

    Ishida Takashi, Hishizawa Masakatsu, Kato Koji, Tanosaki Ryuji, Fukuda Takahiro, Takatsuka Yoshifusa, Eto Tetsuya, Miyazaki Yasushi, Hidaka Michihiro, Uike Naokuni, Miyamoto Toshihiro, Tsudo Mitsuru, Sakamaki Hisashi, Morishima Yasuo, Suzuki Ritsuro, Utsunomiya Atae

    BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION   19 巻 ( 12 ) 頁: 1731 - 1739   2013年12月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Biology of Blood and Marrow Transplantation  

    Allogeneic hematopoietic cell transplantation (HCT), but not autologous HCT, can provide long-term remission in some patients with adult T cell leukemia-lymphoma (ATL). We retrospectively analyzed the effects of acute graft-versus-host disease (GVHD) among the 616 patients with ATL who survived at least 30 days after allogeneic HCT with other than cord blood grafts. Multivariate analyses treating the occurrence of GVHD as a time-varying covariate demonstrated an association between grade I-II acute GVHD and favorable overall survival (OS) (hazard ratio [HR], 0.634; 95% confidence interval [CI], 0.477 to 0.843), whereas grade III-IV acute GVHD showed a trend toward unfavorable OS (HR, 1.380; 95% CI, 0.988 to 1.927) compared with nonacute GVHD. In subsequent multivariate analyses of patients who survived at least 100 days after HCT (n= 431), the presence of limited chronic GVHD showed a trend toward favorable OS (HR, 0.597; 95% CI, 0.354 to 1.007), and extensive chronic GVHD had a significant effect on OS (HR, 0.585; 95% CI, 0.389 to 0.880). There were no significant interactions between myeloablative conditioning or reduced-intensity conditioning with OS even when acute GVHD was absent or present at grade I-II or grade III-IV or when chronic GVHD was absent, limited, or extensive. This study demonstrates the actual existence of graft-versus-ATL effects in patients with ATL regardless of whether myeloablative conditioning or reduced-intensity conditioning is used. © 2013 American Society for Blood and Marrow Transplantation.

    DOI: 10.1016/j.bbmt.2013.09.014

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  123. Global real-time quantitative reverse transcription-polymerase chain reaction detecting proto-oncogenes associated with 14q32 chromosomal translocation as a valuable marker for predicting survival in multiple myeloma.

    Inagaki A, Tajima E, Uranishi M, Totani H, Asao Y, Ogura H, Masaki A, Yoshida T, Mori F, Ito A, Yano H, Ri M, Kayukawa S, Kataoka T, Kusumoto S, Ishida T, Hayami Y, Hanamura I, Komatsu H, Inagaki H, Matsuda Y, Ueda R, Iida S

    Leukemia research   37 巻 ( 12 ) 頁: 1648 - 55   2013年12月

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    記述言語:英語  

    DOI: 10.1016/j.leukres.2013.09.026

    PubMed

  124. 免疫不全マウスを用いた造血器腫瘍の病態解明および治療開発研究

    石田 高司, 伊藤 旭, 上田 龍三

    無菌生物 = Japanese journal of germfree life and gnotobiology   43 巻 ( 1 ) 頁: 63 - 64   2013年9月

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    記述言語:日本語  

  125. [Leukemia: recent progress in diagnosis and treatment. Topics: IV. Recent topics; 1. Novel antibody therapy targeting CCR4 for adult T-cell leukemia/lymphoma].

    Ishida T

    Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine   102 巻 ( 7 ) 頁: 1744 - 50   2013年7月

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    記述言語:日本語   出版者・発行元:Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine  

    成人T細胞性白血病/リンパ腫(adult T-cell leukemia/lymphoma:ATLもしくはATLL)はレトロウイルス,HTLV-1によって引き起こされるリンパ系腫瘍である.ATLの予後は不良であり,化学療法の成績は惨憺たるものである.同種造血幹細胞移植療法で長期生存を得るケースもあるが,全ATLのなかのごく一部に過ぎない.そのような現状のなかATLに対する新規抗体薬(モガムリズマブ)が世界に先駆け日本で薬品製造販売承認を取得した.本稿ではATL治療の現状および,新時代(モガムリズマブ時代)におけるATL治療の展望を概説する.

    DOI: 10.2169/naika.102.1744

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  126. Autologous Tax-specific CTL therapy in a primary adult T cell leukemia/lymphoma cell-bearing NOD/Shi-scid, IL-2Rγnull mouse model. 査読有り

    Masaki A, Ishida T, Suzuki S, Ito A, Mori F, Sato F, Narita T, Yamada T, Ri M, Kusumoto S, Komatsu H, Tanaka Y, Niimi A, Inagaki H, Iida S, Ueda R

    J Immunol.   191 巻 ( 1 ) 頁: 135 - 144   2013年7月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Immunology  

    We expanded human T-lymphotropic virus type 1 Tax-specific CTL in vitro from PBMC of three individual adult T cell leukemia/lymphoma (ATL) patients and assessed their therapeutic potential in an in vivo model using NOG mice bearing primary ATL cells from the respective three patients (ATL/NOG). In these mice established with cells from a chronic-type patient, treatment by i.p. injection of autologous Tax-CTL resulted in greater infiltration of CD8-positive T cells into each ATL lesion. This was associated with a significant decrease of ATL cell infiltration into blood, spleen, and liver. Tax-CTL treatment also significantly decreased human soluble IL-2R concentrations in the sera. In another group of ATL/NOG mice, Tax-CTL treatment led to a significant prolongation of survival time. These findings show that Tax-CTL can infiltrate the tumor site, recognize, and kill autologous ATL cells in mice in vivo. In ATL/NOG mice with cells from an acute-type patient, whose postchemotherapeutic remission continued for >18 mo, antitumor efficacy of adoptive Tax-CTL therapy was also observed. However, in ATL/NOG mice from a different acute-type patient, whose ATL relapsed after 6 mo of remission, no efficacy was observed. Thus, although the therapeutic effects were different for different ATL patients, to the best of our knowledge, this is the first report that adoptive therapy with Ag-specific CTL expanded from a cancer patient confers antitumor effects, leading to significant survival benefit for autologous primary cancer cell-bearing mice in vivo. The present study contributes to research on adoptive CTL therapy, which should be applicable to several types of cancer. Copyright © 2013 by The American Association of Immunologists, Inc.

    DOI: 10.4049/jimmunol.1202692

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  127. Randomized phase II trial of uracil/tegafur and cisplatin versus vinorelbine and cisplatin with concurrent thoracic radiotherapy for locally advanced unresectable stage III non-small-cell lung cancer: NJLCG 0601.

    Sugawara S, Maemondo M, Tachihara M, Inoue A, Ishimoto O, Sakakibara T, Usui K, Watanabe H, Matsubara N, Watanabe K, Kanazawa K, Ishida T, Saijo Y, Nukiwa T, North Japan Lung Cancer Study Group.

    Lung cancer (Amsterdam, Netherlands)   81 巻 ( 1 ) 頁: 91 - 6   2013年7月

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    記述言語:英語  

    DOI: 10.1016/j.lungcan.2013.04.010

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  128. Bath-PUVA therapy decreases infiltrating CCR4-expressing tumor cells and regulatory T cells in patients with mycosis fungoides 査読有り

    Kato H., Saito C., Ito E., Furuhashi T., Nishida E., Ishida T., Ueda R., Inagaki H., Morita A.

    Clinical Lymphoma, Myeloma and Leukemia   13 巻 ( 3 ) 頁: 273 - 280   2013年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Clinical Lymphoma, Myeloma and Leukemia  

    Background: Mycosis fungoides (MF) is a malignant lymphoma characterized by expansion of CD4+ memory T-cell clones. Infiltrating cells express CCR4, which is attracted to CC chemokine ligands 17 and 22 (thymus and activation-regulated chemokine [TARC]/CCL17 and TARC/CCL22). Bath-psoralen plus ultraviolet A (PUVA) is effective against MF. In patients with psoriasis, bath-PUVA induces circulating regulatory T cells (Tregs), which suppress effector T cells. To understand the mechanisms in MF, we analyzed lesion-infiltrating cells before and after bath-PUVA therapy. Patients and Methods: Thirteen patients with MF (12 stage IB, 1 stage III; mean age 69.2 years, range 35-87 years; 6 men, 7 women) were recruited. Results: Immunohistochemical analysis revealed that lesion CCR4-positive (CCR4 +) cells and Tregs significantly decreased from 105.1 ± 164.8 cells/10-2 mm2 to 31.4 ± 39.0 cells/10-2 mm2 and from 78.1 ± 67.8 cells/10-2 mm2 to 24.7 ± 25.0 cells/10-2 mm2, respectively. Serum TARC levels significantly correlated with infiltrating CD3+ (r = 0.997), CCR4+ (r = 0.991), and forkhead box P3-positive (Foxp3 +) cells (r = 0.843). Circulating Tregs before bath-PUVA therapy were not significantly different from those in healthy volunteers. Bath-PUVA did not significantly change the percentage of circulating Tregs. Conclusions: Bath-PUVA decreased CCR4+ cells and Tregs in MF lesions but did not induce circulating Tregs, which might suppress effector T cells. Direct effects through skin lesions might eliminate both pathogenetically relevant cells and Tregs. Systemic immunosuppression was not induced. © 2013 Elsevier Inc.

    DOI: 10.1016/j.clml.2012.12.002

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  129. Development of a novel redirected T-cell-based adoptive immunotherapy targeting human telomerase reverse transcriptase for adult T-cell leukemia. 査読有り

    Miyazaki Y, Fujiwara H, Asai H, Ochi F, Ochi T, Azuma T, Ishida T, Okamoto S, Mineno J, Kuzushima K, Shiku H, Yasukawa M

    Blood   121 巻 ( 24 ) 頁: 4894 - 4901   2013年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blood  

    Although adult T-cell leukemia (ATL) has a poor prognosis, successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) in some cases suggests that a cellular immune-mediated strategy can be effective. So far, however, no effective target for anti-ATL immunotherapy has been defined. Here we demonstrated for the first time that human telomerase reverse transcriptase (hTERT) is a promising therapeutic target for ATL, and we developed a novel redirected T-cell-based immunotherapy targeting hTERT. hTERT messenger RNA was produced abundantly in ATL tumor cells but not in steady-state normal cells. Rearranged human leukocyte antigen-A*24:02 (HLA-A*24:02) -restricted and hTERT461-469 nonameric peptide-specific T-cell receptor (TCR) α/β genes were cloned from our previously established cytotoxic T lymphocyte clone (K3-1) and inserted into a novel retroviral TCR expression vector encoding small interfering RNAs for endogenous TCR genes in redirected T cells (hTERT-siTCR vector). Consequently, allogeneic or autologous gene-modified CD8+ T cells prepared using the hTERT-siTCR vector successfully killed ATL tumor cells, but not normal cells including steady-state hematopoietic progenitors, in an HLA-A*24:02-restricted manner both in vitro and in vivo. Our experimental observations support the development of a novel hTERT-targeting redirected T-cell-based adoptive immunotherapy for ATL patients, especially those for whom suitable allo-HSCT donors are lacking. © 2013 by The American Society of Hematology.

    DOI: 10.1182/blood-2012-11-465971

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  130. Clinical practice guidelines for nursing- and healthcare-associated pneumonia (NHCAP) [Complete translation]

    Kohno S., Imamura Y., Shindo Y., Seki M., Ishida T., Teramoto S., Kadota J., Tomono K., Watanabe A.

    Respiratory Investigation   51 巻 ( 2 ) 頁: 103 - 126   2013年6月

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    記述言語:日本語   出版者・発行元:Respiratory Investigation  

    DOI: 10.1016/j.resinv.2012.11.001

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  131. Successful salvage therapy using lenalidomide in a patient with relapsed multiple myeloma after allogeneic hematopoietic stem cell transplantation

    SUZUKI Tomotaka, KUSUMOTO Shigeru, YOSHIDA Tatsuya, MORI Fumiko, ITO Asahi, RI Masaki, ISHIDA Takashi, KOMATSU Hirokazu, NIIMI Akio, IIDA Shinsuke

    International journal of hematology   97 巻 ( 4 ) 頁: 540 - 543   2013年4月

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    記述言語:英語  

  132. Successful salvage therapy using lenalidomide in a patient with relapsed multiple myeloma after allogeneic hematopoietic stem cell transplantation. 査読有り

    Suzuki T, Kusumoto S, Yoshida T, Mori F, Ito A, Ri M, Ishida T, Komatsu H, Niimi A, Iida S

    International journal of hematology   97 巻 ( 4 ) 頁: 540 - 543   2013年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:International Journal of Hematology  

    DOI: 10.1007/s12185-013-1301-4

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  133. Angioimmunoblastic T-cell lymphoma mice model 査読有り

    Sato F., Ishida T., Ito A., Mori F., Masaki A., Takino H., Narita T., Ri M., Kusumoto S., Suzuki S., Komatsu H., Niimi A., Ueda R., Inagaki H., Iida S.

    Leukemia Research   37 巻 ( 1 ) 頁: 21 - 27   2013年1月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Leukemia Research  

    We established an angioimmunoblastic T-cell lymphoma (AITL) mouse model using NOD/Shi-scid, IL-2Rγnull mice as recipients. The immunohistological findings of the AITL mice were almost identical to those of patients with AITL. In addition, substantial amounts of human immunoglobulin G/A/M were detected in the sera of the AITL mice. This result indicates that AITL tumor cells helped antibody production by B cells or plasma cells. This is the first report of reconstituting follicular helper T (TFH) function in AITL cells in an experimental model, and this is consistent with the theory that TFH cell is the cell of origin of AITL tumor cells. © 2012 Elsevier Ltd.

    DOI: 10.1016/j.leukres.2012.09.009

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  134. Tax is a potential molecular target for immunotherapy of adult T-cell leukemia/lymphoma 査読有り

    Susumu Suzuki, Ayako Masaki, Takashi Ishida, Asahi Ito, Fumiko Mori, Fumihiko Sato, Tomoko Narita, Masaki Ri, Shigeru Kusumoto, Hirokazu Komatsu, Yasuo Fukumori, Hiroyoshi Nishikawa, Yuetsu Tanaka, Akio Niimi, Hiroshi Inagaki, Shinsuke Iida, Ryuzo Ueda

    Cancer Science   103 巻 ( 10 ) 頁: 1764 - 1773   2012年10月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We expanded CTL specific for Tax (a human T-lymphotropic virus type-1-encoded gene product) in vitro from PBMC of several adult T-cell leukemia/lymphoma (ATL) patients, and document its potential significance as a target for ATL immunotherapy. Tax-specific CTL responses against tumor cells were restricted by Tax-expression and the appropriate human leukocyte antigen (HLA) type. Tax-specific CTL recognized HLA/Tax-peptide complexes on autologous ATL cells, even when their Tax expression was so low that it could only be detected by RT-PCR but not by flow cytometry. Recognition resulted in interferon gamma (IFN-γ) production and target cell lysis. This would be the first report that Tax-specific CTL from ATL patients specifically recognized and killed autologous tumor cells that expressed Tax. The Tax-specific CTL responded to as little as 0.01 pM of the corresponding peptide, indicating that their T-cell receptor avidity was much higher than that of any other CTL recognizing viral or other tumor antigens. This is presumably the reason why the Tax-specific CTL recognized and killed autologous ATL cells despite their very low Tax expression. In addition, cell cycle analyses and experiments with primary ATL cell-bearing mice demonstrated that ATL cells present at the site of active cell proliferation, such as in the tumor masses, expressed substantial amounts of Tax, but it was minimally expressed by the tumor cells in a quiescent state, such as in the blood. The present study not only provides a strong rationale for exploiting Tax as a possible target for ATL immunotherapy but also contributes to our understanding of the immunopathogenesis of ATL. © 2012 Japanese Cancer Association.

    DOI: 10.1111/j.1349-7006.2012.02371.x

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  135. Tax is a potential molecular target for immunotherapy of adult T-cell leukemia/lymphoma 査読有り

    Susumu Suzuki, Ayako Masaki, Takashi Ishida, Asahi Ito, Fumiko Mori, Fumihiko Sato, Tomoko Narita, Masaki Ri, Shigeru Kusumoto, Hirokazu Komatsu, Yasuo Fukumori, Hiroyoshi Nishikawa, Yuetsu Tanaka, Akio Niimi, Hiroshi Inagaki, Shinsuke Iida, Ryuzo Ueda

    CANCER SCIENCE   103 巻 ( 10 ) 頁: 1764 - 1773   2012年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    We expanded CTL specific for Tax (a human T-lymphotropic virus type-1-encoded gene product) in similar to vitro from PBMC of several adult T-cell leukemia/lymphoma (ATL) patients, and document its potential significance as a target for ATL immunotherapy. Tax-specific CTL responses against tumor cells were restricted by Tax-expression and the appropriate human leukocyte antigen (HLA) type. Tax-specific CTL recognized HLA/Tax-peptide complexes on autologous ATL cells, even when their Tax expression was so low that it could only be detected by RT-PCR but not by flow cytometry. Recognition resulted in interferon gamma (IFN-?) production and target cell lysis. This would be the first report that Tax-specific CTL from ATL patients specifically recognized and killed autologous tumor cells that expressed Tax. The Tax-specific CTL responded to as little as 0.01 similar to pM of the corresponding peptide, indicating that their T-cell receptor avidity was much higher than that of any other CTL recognizing viral or other tumor antigens. This is presumably the reason why the Tax-specific CTL recognized and killed autologous ATL cells despite their very low Tax expression. In addition, cell cycle analyses and experiments with primary ATL cell-bearing mice demonstrated that ATL cells present at the site of active cell proliferation, such as in the tumor masses, expressed substantial amounts of Tax, but it was minimally expressed by the tumor cells in a quiescent state, such as in the blood. The present study not only provides a strong rationale for exploiting Tax as a possible target for ATL immunotherapy but also contributes to our understanding of the immunopathogenesis of ATL.

    DOI: 10.1111/j.1349-7006.2012.02371.x

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  136. Tax is a potential molecular target for immunotherapy of adult T-cell leukemia/lymphoma

    Suzuki S., Masaki A., Ishida T., Ito A., Mori F., Sato F., Narita T., Ri M., Kusumoto S., Komatsu H., Fukumori Y., Nishikawa H., Tanaka Y., Niimi A., Inagaki H., Iida S., Ueda R.

    Cancer Science   103 巻 ( 10 ) 頁: 1764 - 1773   2012年10月

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    記述言語:日本語   出版者・発行元:Cancer Science  

    We expanded CTL specific for Tax (a human T-lymphotropic virus type-1-encoded gene product) in vitro from PBMC of several adult T-cell leukemia/lymphoma (ATL) patients, and document its potential significance as a target for ATL immunotherapy. Tax-specific CTL responses against tumor cells were restricted by Tax-expression and the appropriate human leukocyte antigen (HLA) type. Tax-specific CTL recognized HLA/Tax-peptide complexes on autologous ATL cells, even when their Tax expression was so low that it could only be detected by RT-PCR but not by flow cytometry. Recognition resulted in interferon gamma (IFN-γ) production and target cell lysis. This would be the first report that Tax-specific CTL from ATL patients specifically recognized and killed autologous tumor cells that expressed Tax. The Tax-specific CTL responded to as little as 0.01 pM of the corresponding peptide, indicating that their T-cell receptor avidity was much higher than that of any other CTL recognizing viral or other tumor antigens. This is presumably the reason why the Tax-specific CTL recognized and killed autologous ATL cells despite their very low Tax expression. In addition, cell cycle analyses and experiments with primary ATL cell-bearing mice demonstrated that ATL cells present at the site of active cell proliferation, such as in the tumor masses, expressed substantial amounts of Tax, but it was minimally expressed by the tumor cells in a quiescent state, such as in the blood. The present study not only provides a strong rationale for exploiting Tax as a possible target for ATL immunotherapy but also contributes to our understanding of the immunopathogenesis of ATL. © 2012 Japanese Cancer Association.

    DOI: 10.1111/j.1349-7006.2012.02371.x

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  137. Allogeneic hematopoietic stem cell transplantation for adult T-cell leukemia-lymphoma with special emphasis on preconditioning regimen: a nationwide retrospective study 査読有り

    Ishida Takashi, Hishizawa Masakatsu, Kato Koji, Tanosaki Ryuji, Fukuda Takahiro, Taniguchi Shuichi, Eto Tetsuya, Takatsuka Yoshifusa, Miyazaki Yasushi, Moriuchi Yukiyoshi, Hidaka Michihiro, Akashi Koichi, Uike Naokuni, Sakamaki Hisashi, Morishima Yasuo, Kato Koji, Suzuki Ritsuro, Nishiyama Takeshi, Utsunomiya Atae

    BLOOD   120 巻 ( 8 ) 頁: 1734 - 1741   2012年8月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blood  

    Adult T-cell leukemia-lymphoma (ATL) is an intractable mature T-cell neoplasm. We performed a nationwide retrospective study of allogeneic hematopoietic stem cell transplantation (HSCT) for ATL in Japan, with special emphasis on the effects of the preconditioning regimen. This is the largest study ofATL patients receiving HSCT. Median overall survival (OS) and 3-year OS of bone marrow or peripheral blood transplantation recipients (n = 586) was 9.9 months (95% confidence interval, 7.4-13.2 months) and 36% (32%-41%), respectively. These values for recipients of myeloablative conditioning (MAC; n = 280) and reduced intensity conditioning (RIC; n = 306) were 9.5 months (6.7-18.0 months) and 39% (33%-45%) and 10.0 months (7.2-14.0 months) and 34% (29%-40%), respectively. Multivariate analysis demonstrated 5 significant variables contributing to poorer OS, namely, older age, male sex, not in complete remission, poor performance status, and transplantation from unrelated donors. Although no significant difference in OS between MAC and RIC was observed, there was a trend indicating that RIC contributed to better OS in older patients. Regarding mortality, RIC was significantly associated with ATL-related mortality compared with MAC. In conclusion, allogeneic HSCT not only with MAC but also with RIC is an effective treatment resulting in long-term survival in selected patients with ATL. © 2012 by The American Society of Hematology.

    DOI: 10.1182/blood-2012-03-414490

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  138. Forkhead box P1 overexpression and its clinicopathologic significance in peripheral T-cell lymphoma, not otherwise specified

    Yamada S., Sato F., Xia H., Takino H., Kominato S., Ri M., Ishida T., Iida S., Inagaki H., Yamada K.

    Human Pathology   43 巻 ( 8 ) 頁: 1322 - 1327   2012年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Human Pathology  

    Forkhead box P1 protein is a transcription factor involved in cell signaling and regulation of gene expression and is essential for B-cell development. Forkhead box P1 overexpression has been associated with a worsened prognosis in some B-cell lymphomas. However, little is known about the clinicopathologic significance of forkhead box P1 in T-cell malignancies. In this study, immunohistochemistry for forkhead box P1 was performed in peripheral T-cell lymphoma, not otherwise specified, cases (n = 41), which were then divided into lower (n = 15) and higher (n = 26) forkhead box P1 expressers. Results of real-time quantitative reverse transcriptase polymerase chain reaction for forkhead box P1 messenger RNA supported the data on immunohistochemical forkhead box P1 expression. Forkhead box P1 overexpression in lymphoma cells was inversely associated with proliferation activity as evaluated by Ki-67 expression. Double immunostain for forkhead box P1 and a T-cell marker in normal lymph nodes showed forkhead box P1 signals in many of nonneoplastic T cells. Prognostic analysis showed that forkhead box P1 overexpression was associated with an improved overall survival of the patients with peripheral T-cell lymphoma, not otherwise specified, and was independent of the International Prognostic Index in multivariate analysis. Forkhead box P1 overexpression may be associated with less activated phenotype of the tumors and with a better prognosis in patients with peripheral T-cell lymphoma, not otherwise specified. The clinicopathologic significance of forkhead box P1 overexpression in peripheral T-cell lymphoma, not otherwise specified, may be different from that in B-cell lymphomas. © 2012 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.humpath.2011.10.013

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  139. Identification of Toyocamycin, an agent cytotoxic for multiple myeloma cells, as a potent inhibitor of ER stress-induced XBP1 mRNA splicing 査読有り

    Ri M., Tashiro E., Oikawa D., Shinjo S., Tokuda M., Yokouchi Y., Narita T., Masaki A., Ito A., Ding J., Kusumoto S., Ishida T., Komatsu H., Shiotsu Y., Ueda R., Iwawaki T., Imoto M., Iida S.

    Blood Cancer Journal   2 巻 ( 7 ) 頁: e79   2012年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Blood Cancer Journal  

    The IRE1a-XBP1 pathway, a key component of the endoplasmic reticulum (ER) stress response, is considered to be a critical regulator for survival of multiple myeloma (MM) cells. Therefore, the availability of small-molecule inhibitors targeting this pathway would offer a new chemotherapeutic strategy for MM. Here, we screened small-molecule inhibitors of ER stress-induced XBP1 activation, and identified toyocamycin from a culture broth of an Actinomycete strain. Toyocamycin was shown to suppress thapsigargin-, tunicamycin- and 2-deoxyglucose-induced XBP1 mRNA splicing in HeLa cells without affecting activating transcription factor 6 (ATF6) and PKR-like ER kinase (PERK) activation. Furthermore, although toyocamycin was unable to inhibit IRE1α phosphorylation, it prevented IRE1α-induced XBP1 mRNA cleavage in vitro. Thus, toyocamycin is an inhibitor of IRE1α-induced XBP1 mRNA cleavage. Toyocamycin inhibited not only ER stress-induced but also constitutive activation of XBP1 expression in MM lines as well as primary samples from patients. It showed synergistic effects with bortezomib, and induced apoptosis of MM cells including bortezomib-resistant cells at nanomolar levels in a dose-dependent manner. It also inhibited growth of xenografts in an in vivo model of human MM. Taken together, our results suggest toyocamycin as a lead compound for developing anti-MM therapy and XBP1 as an appropriate molecular target for anti-MM therapy. © 2012 Macmillan Publishers Limited All rights reserved.

    DOI: 10.1038/bcj.2012.26

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  140. Potent antitumor effects of bevacizumab in a microenvironment-dependent human lymphoma mouse model 査読有り

    F. Mori, T. Ishida, A. Ito, F. Sato, A. Masaki, H. Takino, M. Ri, S. Kusumoto, H. Komatsu, R. Ueda, H. Inagaki, S. Iida

    BLOOD CANCER JOURNAL   2 巻 ( 4 ) 頁: e67   2012年4月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    We established a mouse model of microenvironment-dependent human lymphoma, and assessed the therapeutic potential of bevacizumab, an antitumor agent acting on the microenvironment. NOD/Shi-scid, IL-2R gamma(null) (NOG) mice were used as recipients of primary tumor cells from a patient with diffuse large B-cell lymphoma (DLBCL), which engraft and proliferate in a microenvironment-dependent manner. The lymphoma cells could be serially transplanted in NOG mice, but could not be maintained in in vitro cultures. Injection of bevacizumab together with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) significantly increased necrosis and decreased vascularization in the tumor, compared with CHOP alone. Levels of human soluble interleukin-2 receptor (sIL2R) in the serum of bevacizumab+CHOP-treated mice (reflecting the DLBCL tumor burden) were significantly lower than in CHOP recipients. Mice receiving bevacizumab monotherapy also showed significant benefit in terms of tumor necrosis and vascularization, as well as decreased serum sIL2R concentrations. The present DLBCL model reflects the human DLBCL in vivo environment more appropriately than current mouse models using established tumor cell lines. This is the first report to evaluate the efficacy of bevacizumab in such a tumor microenvironment-dependent model. Bevacizumab may be a potential treatment strategy for DLBCL patients.

    DOI: 10.1038/bcj.2012.12

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  141. Cancer/testis antigens are novel targets of immunotherapy for adult T-cell leukemia/lymphoma 査読有り

    Hiroyoshi Nishikawa, Yuka Maeda, Takashi Ishida, Sacha Gnjatic, Eiichi Sato, Fumiko Mori, Daisuke Sugiyama, Asahi Ito, Yasuo Fukumori, Atae Utsunomiya, Hiroshi Inagaki, Lloyd J. Old, Ryuzo Ueda, Shimon Sakaguchi

    BLOOD   119 巻 ( 13 ) 頁: 3097 - 3104   2012年3月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC HEMATOLOGY  

    Adult T-cell leukemia/lymphoma (ATLL) is an intractable hematologic malignancy caused by human T-lymphotropic virus type 1 (HTLV-1), which infects approximately 20 million people worldwide. Here, we have explored the possible expression of cancer/testis (CT) antigens by ATLL cells, as CT antigens are widely recognized as ideal targets of cancer immunotherapy against solid tumors. A high percentage (87.7%) of ATLL cases (n = 57) expressed CT antigens at the mRNA level: NY-ESO-1 (61.4%), MAGE-A3 (31.6%), and MAGE-A4 (61.4%). CT antigen expression was confirmed by immunohistochemistry. This contrasts with other types of lymphoma or leukemia, which scarcely express these CT antigens. Humoral immune responses, particularly against NY-ESO-1, were detected in 11.6% (5 of 43) and NY-ESO-1-specific CD8(+) T-cell responses were observed in 55.6% (5 of 9) of ATLL patients. NY-ESO-1-specific CD8(+) T cells recognized autologous ATLL cells and produced effector cytokines. Thus, ATLL cells characteristically express CT antigens and therefore vaccination with CT antigens can be an effective immunotherapy of ATLL. (Blood. 2012;119(13):3097-3104)

    DOI: 10.1182/blood-2011-09-379982

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  142. Antibody therapy for Adult T-cell leukemia-lymphoma

    ISHIDA Takashi, UEDA Ryuzo

    International journal of hematology   94 巻 ( 5 ) 頁: 443 - 452   2011年11月

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    記述言語:英語  

  143. Antibody therapy for Adult T-cell leukemia-lymphoma 査読有り

    Takashi Ishida, Ryuzo Ueda

    INTERNATIONAL JOURNAL OF HEMATOLOGY   94 巻 ( 5 ) 頁: 443 - 452   2011年11月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER TOKYO  

    Adult T-cell leukemia-lymphoma (ATL) has a very poor prognosis. Since there currently are limited treatment options for ATL patients, several novel agents are being developed and tested clinically. Antibody therapy against ATL was initially started with interleukin-2 receptor alpha-subunit, CD25, as a target molecule in the late 1980s, and is currently ongoing. CC chemokine receptor 4 (CCR4) was postulated as a novel molecular target in ATL antibody therapy, and humanized anti-CCR4 mAb (KW-0761), whose Fc region was defucosylated to enhance antibody-dependent cellular cytotoxicity, was developed. A phase I study of KW-0761 in relapsed ATL and peripheral T-cell lymphoma was started in 2006, and a subsequent phase II study was completed in 2010. KW-0761 showed a clinically meaningful antitumor activity in patients with relapsed ATL, with an acceptable toxicity profile. The prognosis of ATL patients should be improved in the near future with clinical applications of novel treatment strategies, including those involving KW-0761 and other promising antibody therapies targeting CD25 or CD30.

    DOI: 10.1007/s12185-011-0941-5

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  144. Immunopathogenesis of lymphoma : Focus on CCR4

    ISHIDA Takashi, UEDA Ryuzo

    Cancer science   102 巻 ( 1 ) 頁: 44 - 50   2011年1月

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    記述言語:英語  

  145. Immunopathogenesis of lymphoma: Focus on CCR4 査読有り

    Takashi Ishida, Ryuzo Ueda

    CANCER SCIENCE   102 巻 ( 1 ) 頁: 44 - 50   2011年1月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL PUBLISHING, INC  

    Evading immune surveillance is one of the common hallmarks of cancer. Herein we describe two major evasion mechanisms in lymphoma, focusing on regulatory T (Treg) cells and C-C chemokine receptor 4 (CCR4) expressed on these cells. First, the tumor cells themselves function as Treg cells, characterized by expression of CCR4, contributing to tumor survival by downregulating host immunity. Second, CCR4 ligands are produced by tumor cells, which attract other CCR4+ Treg cells to the vicinity of the tumor. CCR4+ adult T-cell leukemia//lymphoma is an example of the former phenomenon, and Hodgkin lymphoma of the latter, for which an almost identical immunopathogenesis has been reported in many types of cancer. Awareness of the importance of CCR4 allows the rational design of more effective cancer treatments. Accordingly, we have developed a defucosylated anti-CCR4 mAb, the first therapeutic agent targeting CCR4 to be used clinically for cancer. The therapeutic anti-CCR4 mAb represents a promising treatment method for patients with CCR4+ neoplasms by directly killing the cancer cells, but could also be used as a novel treatment strategy for many types of CCR4- cancers to overcome the suppressive effect of CCR4+ Treg cells. (Cancer Sci 2011; 102: 44-50).

    DOI: 10.1111/j.1349-7006.2010.01767.x

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  146. A complement-dependent cytotoxicity-enhancing anti-CD20 antibody mediating potent antitumor activity in the humanized NOD/Shi-scid, IL-2Rγ(null) mouse lymphoma model. 査読有り

    Sato F, Ito A, Ishida T, Mori F, Takino H, Inagaki A, Ri M, Kusumoto S, Komatsu H, Iida S, Okada N, Inagaki H, Ueda R

    Cancer Immunol Immunother.   59 巻 ( 12 ) 頁: 1791 - 1800   2010年12月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/s00262-010-0905-2

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  147. Bortezomib-resistant myeloma cell lines: a role for mutated PSMB5 in preventing the accumulation of unfolded proteins and fatal ER stress 査読有り

    M. Ri, S. Iida, T. Nakashima, H. Miyazaki, F. Mori, A. Ito, A. Inagaki, S. Kusumoto, T. Ishida, H. Komatsu, Y. Shiotsu, R. Ueda

    LEUKEMIA   24 巻 ( 8 ) 頁: 1506 - 1512   2010年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Bortezomib is an effective agent for treating multiple myeloma (MM). To investigate the underlying mechanisms associated with acquired resistance to this agent, we established two bortezomib-resistant MM cell lines, KMS-11/BTZ and OPM-2/BTZ, the 50% inhibitory concentration values of which were respectively 24.7- and 16.6-fold higher than their parental cell lines. No activation of caspase and BH3-only proteins such as Noxa was noted in bortezomib-resistant cells after exposure to the drug. The accumulation of polyubiquitinated proteins was reduced in bortezomib-resistant cells compared with the parental cells, associated with avoidance of catastrophic ER stress as assessed by downregulation of CHOP expression. These resistant MM cells have a unique point mutation, G322A, in the gene encoding the proteasome beta 5 subunit (PSMB5), likely resulting in conformational changes to the bortezomib-binding pocket of this subunit. KMS-11 parental cells transfected to express mutated PSMB5 also showed reduced bortezomib-induced apoptosis compared with those expressing wild-type PSMB5 or the parental cells. Expression of mutated PSMB5 was associated with the prevention of the accumulation of unfolded proteins. Thus, a fraction of MM cells may acquire bortezomib resistance by suppressing apoptotic signals through the inhibition of unfolded protein accumulation and subsequent excessive ER stress by a mutation of the PSMB5 gene. Leukemia (2010) 24, 1506-1512; doi:10.1038/leu.2010.137;published online 17 June 2010

    DOI: 10.1038/leu.2010.137

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  148. Reactivation of hepatitis B virus in HBsAg-negative patients with multiple myeloma : two case reports

    YOSHIDA Tatsuya, KUSUMOTO Shigeru, INAGAKI Atsushi, MORI Fumiko, ITO Asahi, RI Masaki, ISHIDA Takashi, KOMATSU Hirokazu, IIDA Shinsuke, SUGAUCHI Fuminaka, TANAKA Yasuhito, MIZOKAMI Masashi, UEDA Ryuzo

    International journal of hematology   91 巻 ( 5 ) 頁: 844 - 849   2010年6月

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    記述言語:英語  

  149. Reactivation of hepatitis B virus in HBsAg-negative patients with multiple myeloma: two case reports 査読有り

    Tatsuya Yoshida, Shigeru Kusumoto, Atsushi Inagaki, Fumiko Mori, Asahi Ito, Masaki Ri, Takashi Ishida, Hirokazu Komatsu, Shinsuke Iida, Fuminaka Sugauchi, Yasuhito Tanaka, Masashi Mizokami, Ryuzo Ueda

    INTERNATIONAL JOURNAL OF HEMATOLOGY   91 巻 ( 5 ) 頁: 844 - 849   2010年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER TOKYO  

    It was recently reported that hepatitis B virus (HBV) reactivation had occurred in HBsAg-negative lymphoma patients who received rituximab plus steroid combination chemotherapy. HBV reactivation in myeloma patients have not been reported extensively. We describe here two cases of HBV reactivation in HBsAg-negative myeloma patients receiving systemic chemotherapy: one from the medical records of 40 patients and another from 61 patients with prospective HBV-DNA monitoring. In the first case positive for anti-HBs, HBV reactivation was diagnosed when hepatitis developed during conventional chemotherapy such as MP and MCP regimen in a relapsed patient after autologous stem cell transplantation (APBSCT); in the second case positive for anti-HBc and anti-HBs, elevation of HBV-DNA was recognized by serial HBV-DNA monitoring performed prospectively following APBSCT. Interestingly, these two cases had the reduction of the titer of anti-HBs during the treatment, followed by HBV reactivation. These clinical data suggest that the HBV-DNA monitoring is necessary for not only HBsAg-positive but also HBsAg-negative myeloma patients with anti-HBc-positive and/or anti-HBs-positive following transplantation and after conventional chemotherapy in the salvage setting. Establishment of a standard strategy to prevent HBV reactivation is important for myeloma patients receiving systemic chemotherapy.

    DOI: 10.1007/s12185-010-0592-y

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  150. Phase I Study of KW-0761, a Defucosylated Humanized Anti-CCR4 Antibody, in Relapsed Patients With Adult T-Cell Leukemia-Lymphoma and Peripheral T-Cell Lymphoma 査読有り

    Yamamoto Kazuhito, Utsunomiya Atae, Tobinai Kensei, Tsukasaki Kunihiro, Uike Naokuni, Uozumi Kimiharu, Yamaguchi Kazunari, Yamada Yasuaki, Hanada Shuichi, Tamura Kazuo, Nakamura Shigeo, Inagaki Hiroshi, Ohshima Koichi, Kiyoi Hitoshi, Ishida Takashi, Matsushima Kouji, Akinaga Shiro, Ogura Michinori, Tomonaga Masao, Ueda Ryuzo

    JOURNAL OF CLINICAL ONCOLOGY   28 巻 ( 9 ) 頁: 1591 - 1598   2010年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1200/JCO.2009.25.3575

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  151. 成人T細胞白血病/リンパ腫に対する新しい治療法の開発

    Medical Practice   vol.27, no.2, 305-307 巻   2010年

  152. [Anti-CCR4 monoclonal antibody as a novel therapy for advanced mycosis fungoides and Sézary syndrome]. 査読有り

    Yano H, Ishida T, Inagaki A, Ishii T, Ri M, Ito A, Kusumoto S, Komatsu H, Iida S, Inagaki H, Ueda R

    [Rinsho ketsueki] The Japanese journal of clinical hematology   50 巻 ( 12 ) 頁: 1671 - 1678   2009年12月

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  153. Defucosylated Anti-CCR4 Monoclonal Antibody Exerts Potent ADCC against Primary ATLL Cells Mediated by Autologous Human Immune Cells in NOD/Shi-scid, IL-2R gamma(null) Mice In Vivo 査読有り

    Asahi Ito, Takashi Ishida, Atae Utsunomiya, Fumihiko Sato, Fumiko Mori, Hiroki Yano, Atsushi Inagaki, Susumu Suzuki, Hisashi Takino, Masaki Ri, Shigeru Kusumoto, Hirokazu Komatsu, Shinsuke Iida, Hiroshi Inagaki, Ryuzo Ueda

    JOURNAL OF IMMUNOLOGY   183 巻 ( 7 ) 頁: 4782 - 4791   2009年10月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC IMMUNOLOGISTS  

    There is a lack of suitable small animal models to evaluate human Ab-dependent cellular cytotoxicity (ADCC) in vivo, because of the species incompatibility between humans and animals or due to nonspecific allogeneic immune reactions. To overcome these problems, we established a human tumor-bearing mouse model, using NOD/Shi-scid, IL-2R gamma(null) (NOG) mice as recipients, in which autologous human immune cells are engrafted and mediate ADCC but in which endogenous murine cells are unable to mediate ADCC. In the present study, we used NOG mice bearing primary adult T cell leukemia/lymphoma (ATLL) cells and a therapeutic chimeric anti-CCR4 mAb, the Fc region of which is defucosylated to enhance ADCC. We report significant antitumor activity in vivo associated with robust ADCC mediated by autologous effector cells from the same patients. The present study is the first to report a mouse model in which a potent antitumor effect of the therapeutic mAb against primary tumor cells is mediated by autologous human immune cells. Human autologous ADCC in mice in vivo was confirmed by the depletion of human immune cells before ATLL PBMC inoculation. In addition, NOG mice bearing primary ATLL cells presented features identical with patients with ATLL. In conclusion, this approach makes it possible to model the human immune system active in Ab-based immunotherapy in vivo, and thus to perform more appropriate preclinical evaluations of novel therapeutic mAb. Furthermore, the potent ADCC mediated by defucosylated anti-CCR4 mAb, observed here in vivo in humanized mice, will be exploited in clinical trials in the near future. The Journal of Immunology, 2009, 183: 4782-4791.

    DOI: 10.4049/jimmunol.0900699

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  154. The Asn505 mutation of the c-MPL gene, which causes familial essential thrombocythemia, induces autonomous homodimerization of the c-Mpl protein due to strong amino acid polarity 査読有り

    Jianmin Ding, Hirokazu Komatsu, Shinsuke Iida, Hiroki Yano, Shigeru Kusumoto, Atsushi Inagaki, Fumiko Mori, Masaki Ri, Asahi Ito, Atsushi Wakita, Takashi Ishida, Masakazu Nitta, Ryuzo Ueda

    BLOOD   114 巻 ( 15 ) 頁: 3325 - 3328   2009年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC HEMATOLOGY  

    We previously reported that a dominant-positive activating mutation (Asn505) in the transmembrane domain (TMD) of c-MPL, which encodes the thrombopoietin receptor, caused familial essential thrombocythemia. Here, we show that the Asn505 mutation induces both autonomous dimerization of c-Mpl and signal activation in the absence of its ligand. Signal activation was preserved in a truncated mutant of Asn505 that lacked the extracellular domain of c-MPL. We also found that the substitution of the amino acid (AA) residue at position 505 with others of strong polarity (Glu, Asp, or Gln) also resulted in activated dimerization without ligand stimulation. Overall, these data show that the Asn505 mutation transduced the signal through the autonomous dimerization of the c-MPL protein due to strong AA polarity. This finding provides a new insight into the mechanism of disease causation by mutations in the TMD of cytokine/hematopoietic receptors. (Blood. 2009; 114: 3325-3328)

    DOI: 10.1182/blood-2008-04-149047

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    PubMed

  155. The Asn505 mutation of the c-MPL gene, which causes familial essential thrombocythemia, induces autonomous homodimerization of the c-Mpl protein due to strong amino acid polarity 査読有り

    Jianmin Ding, Hirokazu Komatsu, Shinsuke Iida, Hiroki Yano, Shigeru Kusumoto, Atsushi Inagaki, Fumiko Mori, Masaki Ri, Asahi Ito, Atsushi Wakita, Takashi Ishida, Masakazu Nitta, Ryuzo Ueda

    BLOOD   114 巻 ( 15 ) 頁: 3325 - 3328   2009年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC HEMATOLOGY  

    We previously reported that a dominant-positive activating mutation (Asn505) in the transmembrane domain (TMD) of c-MPL, which encodes the thrombopoietin receptor, caused familial essential thrombocythemia. Here, we show that the Asn505 mutation induces both autonomous dimerization of c-Mpl and signal activation in the absence of its ligand. Signal activation was preserved in a truncated mutant of Asn505 that lacked the extracellular domain of c-MPL. We also found that the substitution of the amino acid (AA) residue at position 505 with others of strong polarity (Glu, Asp, or Gln) also resulted in activated dimerization without ligand stimulation. Overall, these data show that the Asn505 mutation transduced the signal through the autonomous dimerization of the c-MPL protein due to strong AA polarity. This finding provides a new insight into the mechanism of disease causation by mutations in the TMD of cytokine/hematopoietic receptors. (Blood. 2009; 114: 3325-3328)

    DOI: 10.1182/blood-2008-04-149047

    Web of Science

  156. The Asn505 mutation of the c-MPL gene, which causes familial essential thrombocythemia, induces autonomous homodimerization of the c-Mpl protein due to strong amino acid polarity

    Jianmin Ding, Hirokazu Komatsu, Shinsuke Iida, Hiroki Yano, Shigeru Kusumoto, Atsushi Inagaki, Fumiko Mori, Masaki Ri, Asahi Ito, Atsushi Wakita, Takashi Ishida, Masakazu Nitta, Ryuzo Ueda

    BLOOD   114 巻 ( 15 ) 頁: 3325 - 3328   2009年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC HEMATOLOGY  

    We previously reported that a dominant-positive activating mutation (Asn505) in the transmembrane domain (TMD) of c-MPL, which encodes the thrombopoietin receptor, caused familial essential thrombocythemia. Here, we show that the Asn505 mutation induces both autonomous dimerization of c-Mpl and signal activation in the absence of its ligand. Signal activation was preserved in a truncated mutant of Asn505 that lacked the extracellular domain of c-MPL. We also found that the substitution of the amino acid (AA) residue at position 505 with others of strong polarity (Glu, Asp, or Gln) also resulted in activated dimerization without ligand stimulation. Overall, these data show that the Asn505 mutation transduced the signal through the autonomous dimerization of the c-MPL protein due to strong AA polarity. This finding provides a new insight into the mechanism of disease causation by mutations in the TMD of cytokine/hematopoietic receptors. (Blood. 2009; 114: 3325-3328)

    DOI: 10.1182/blood-2008-04-149047

    Web of Science

  157. Current status and future directions of antibody-based cancer therapy

    Ito A., Ishida T., Ueda R.

    Biotherapy   23 巻 ( 5 ) 頁: 337 - 345   2009年9月

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    記述言語:日本語   出版者・発行元:Biotherapy  

    Therapeutic monoclonal antibodies (mAb) for the treatment of cancer have begun to fulfill their promise over the last several years, as exemplified by the great success of mAb such as rituximab, trastuzumab, cetuximab, panitumumab, and bevacizumab. For a decade or more after the advent of hybridoma production (1975), important technologies required for the clinical application of therapeutic mAb, such as chimerization, humanization and the generation of fully human antibodies, continued to be developed. Currently, next-generation antibody engineering, such as ADCC or CDC enhancement, and extending the half-life of antibody in vivo is at the translational stage from laboratory to clinic. Of these approaches, we ourselves have focused on ADCC, and have developed a chimeric/humanized anti-CCR4 mAb, the Fc region of which is defucosylated. This results in highly enhanced ADCC due to increased binding affinity of the antibody to the Fcr receptor on effector cells. Based on our laboratory work on CCR4, we are currently conducting clinical trials of this defucosylated humanized anti-CCR4 mAb in Japan. We hope that our translational research on CCR4 will provide a good model for the development of anticancer agents including next-generation therapeutic mAb in Japan. In the future, further development of antibody engineering together with improvement of the infrastructure within which we carry out bench to bedside translational research would result in improved outcomes for patients with different types of cancer.

    Scopus

  158. Defucosylated anti-CCR4 monoclonal antibody exercises potent ADCC-mediated antitumor effect in the novel tumor-bearing humanized NOD/Shi-scid, IL-2R gamma(null) mouse model 査読有り

    Asahi Ito, Takashi Ishida, Hiroki Yano, Atsushi Inagaki, Susumu Suzuki, Fumihiko Sato, Hisashi Takino, Fumiko Mori, Masaki Ri, Shigeru Kusumoto, Hirokazu Komatsu, Shinsuke Iida, Hiroshi Inagaki, Ryuzo Ueda

    CANCER IMMUNOLOGY IMMUNOTHERAPY   58 巻 ( 8 ) 頁: 1195 - 1206   2009年8月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    There are no suitable small animal models to evaluate human antibody-dependent cellular cytotoxicity (ADCC) in vivo, due to species incompatibilities. Thus, the first aim of this study was to establish a human tumor-bearing mouse model in which human immune cells can engraft and mediate ADCC, but where the endogenous mouse immune cells cannot mediate ADCC. The second aim was to evaluate ADCC mediated in these humanized mice by the defucosylated anti-CC chemokine receptor 4 (CCR4) monoclonal antibody (mAb) which we have developed and which is now in phase I clinical trials.
    NOD/Shi-scid, IL-2R gamma(null) (NOG) mice were the recipients of human immune cells, and CCR4-expressing Hodgkin lymphoma (HL) and cutaneous T-cell lymphoma (CTCL) cell lines were used as target tumors.
    Humanized mice have been established using NOG mice. The chimeric defucosylated anti-CCR4 mAb KM2760 showed potent antitumor activity mediated by robust ADCC in these humanized mice bearing the HL or CTCL cell lines. KM2760 significantly increased the number of tumor-infiltrating CD56-positive NK cells which mediate ADCC, and reduced the number of tumor-infiltrating FOXP3-positive regulatory T (Treg) cells in HL-bearing humanized mice.
    Anti-CCR4 mAb could be an ideal treatment modality for many different cancers, not only to directly kill CCR4-expressing tumor cells, but also to overcome the suppressive effect of Treg cells on the host immune response to tumor cells. In addition, using our humanized mice, we can perform the appropriate preclinical evaluation of many types of antibody based immunotherapy.

    DOI: 10.1007/s00262-008-0632-0

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  159. Expression of the ULBP ligands for NKG2D by B-NHL cells plays an important role in determining their susceptibility to rituximab-induced ADCC

    Atsushi Inagaki, Takashi Ishida, Hiroki Yano, Toshihiko Ishii, Shigeru Kusumoto, Asahi Ito, Masaki Ri, Fumiko Mori, Jianmin Ding, Hirokazu Komatsu, Shinsuke Iida, Ryuzo Ueda

    INTERNATIONAL JOURNAL OF CANCER   125 巻 ( 1 ) 頁: 212 - 221   2009年7月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Anti body-dependent cellular cytotoxicity (ADCC) is a major antitumor mechanism of action of therapeutic monoclonal antibodies (mAbs). The aim of this study was to identify tumor-associated factors which determine susceptibility to rituximab-induced ADCC. Thirty different CD20+ non-Hodgkin lymphoma cell lines were phenotyped for characteristics such as level of expression of NKG2D ligands, and the influence thereof on susceptibility to rituximab-induced ADCC was established. The present study demonstrated that tumor cell susceptibility to rituximab-induced ADCC was determined by 3 major tumor-associated factors: (i) the amount of the target molecule, CD20; (ii) the amount of the ligands for inhibitory killer Ig-like receptors, major histocompatibility complex class 1; and (iii) the amounts of some of the NKG2D ligands, especially UL16-binding protein (ULBP) 1-3. The importance of the ULBPs was confirmed using antibody blockade. In conclusion., this is the first report to show the importance for rituximab-induced ADCC of ULBPs expressed on tumor cells. The ULBPs could be valuable diagnostic biological markers and significant targets for immunotherapy to improve efficacy not only of rituximab but also of other therapeutic mAbs. (C) 2009 UICC

    DOI: 10.1002/ijc.24351

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  160. Bortezomib-induced apoptosis in mature T-cell lymphoma cells partially depends on upregulation of Noxa and functional repression of Mcl-1

    RI Masaki, IIDA Shinsuke, ISHIDA Takashi, ITO Asahi, YANO Hiroki, INAGAKI Atsushi, DING Jianmin, KUSUMOTO Shigeru, KOMATSU Hirokazu, UTSUNOMIYA Atae, UEDA Ryuzo

    Cancer science   100 巻 ( 2 ) 頁: 341 - 348   2009年2月

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    記述言語:英語  

  161. Bortezomib-induced apoptosis in mature T-cell lymphoma cells partially depends on upregulation of Noxa and functional repression of Mcl-1

    Masaki Ri, Shinsuke Iida, Takashi Ishida, Asahi Ito, Hiroki Yano, Atsushi Inagaki, Jianmin Ding, Shigeru Kusumoto, Hirokazu Komatsu, Atae Utsunomiya, Ryuzo Ueda

    CANCER SCIENCE   100 巻 ( 2 ) 頁: 341 - 348   2009年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL PUBLISHING, INC  

    Bortezomib, a proteasome inhibitor that was originally developed as an inhibitor of nuclear factor-kappa B pathways, is currently used for the treatment of multiple myeloma (MM) and mantle cell lymphoma (MCL). The mechanisms of action of this antitumor agent have been studied by several investigators. Here, we explore the underlying mechanisms of bortezomib-induced apoptosis in cutaneous T-cell lymphoma (CTCL) and adult T-cell leukemia/lymphoma (ATLL) at the level of mitochondrial membrane injury. In all cell lines including (KMS-12-PE [MM], HUT78 [CTCL], ATN1 [ATLL], and MT4 [ATLL]), antiapoptotic factors such as c-Flip and XIAP were downregulated after exposure to bortezomib, probably via inhibition of nuclear factor-kappa B signaling. In addition, among the members of the BH3-only family, upregulation of Noxa was consistently seen at both the transcriptional and protein levels in a p53-independent manner after exposure to bortezomib. Repression of Noxa by small interfering RNA partially rescued CTCL and ATLL cells from bortezomib-induced apoptosis. Immunoprecipitation assays indicated time-dependent binding of Noxa and Mcl-1 in all cell types, suggesting that functional repression of Mcl-1 led to the loss of mitochondrial outer membrane potential. Similar results were also obtained in primary tumor cells from patients with ATLL. Taken together, we conclude that bortezomib-induced apoptosis in ATLL and CTCL cells at least partly depends on the upregulation of Noxa and functional repression of Mcl-1, as is also the case in MM and malignant melanoma. (Cancer Sci 2009; 100: 341-348).

    DOI: 10.1111/j.1349-7006.2008.01038.x

    Web of Science

  162. Bortezomib-induced apoptosis in mature T-cell lymphoma cells partially depends on upregulation of Noxa and functional repression of Mcl-1 査読有り

    Masaki Ri, Shinsuke Iida, Takashi Ishida, Asahi Ito, Hiroki Yano, Atsushi Inagaki, Jianmin Ding, Shigeru Kusumoto, Hirokazu Komatsu, Atae Utsunomiya, Ryuzo Ueda

    CANCER SCIENCE   100 巻 ( 2 ) 頁: 341 - 348   2009年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL PUBLISHING, INC  

    Bortezomib, a proteasome inhibitor that was originally developed as an inhibitor of nuclear factor-kappa B pathways, is currently used for the treatment of multiple myeloma (MM) and mantle cell lymphoma (MCL). The mechanisms of action of this antitumor agent have been studied by several investigators. Here, we explore the underlying mechanisms of bortezomib-induced apoptosis in cutaneous T-cell lymphoma (CTCL) and adult T-cell leukemia/lymphoma (ATLL) at the level of mitochondrial membrane injury. In all cell lines including (KMS-12-PE [MM], HUT78 [CTCL], ATN1 [ATLL], and MT4 [ATLL]), antiapoptotic factors such as c-Flip and XIAP were downregulated after exposure to bortezomib, probably via inhibition of nuclear factor-kappa B signaling. In addition, among the members of the BH3-only family, upregulation of Noxa was consistently seen at both the transcriptional and protein levels in a p53-independent manner after exposure to bortezomib. Repression of Noxa by small interfering RNA partially rescued CTCL and ATLL cells from bortezomib-induced apoptosis. Immunoprecipitation assays indicated time-dependent binding of Noxa and Mcl-1 in all cell types, suggesting that functional repression of Mcl-1 led to the loss of mitochondrial outer membrane potential. Similar results were also obtained in primary tumor cells from patients with ATLL. Taken together, we conclude that bortezomib-induced apoptosis in ATLL and CTCL cells at least partly depends on the upregulation of Noxa and functional repression of Mcl-1, as is also the case in MM and malignant melanoma. (Cancer Sci 2009; 100: 341-348).

    DOI: 10.1111/j.1349-7006.2008.01038.x

    Web of Science

  163. CCR4 を分子標的とするmycosis fungoides/Sezary syndrome に対する新規抗体療法

    臨床血液   Vol.50 No.12 1671-1678 巻   2009年

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  164. がんに対する抗体療法

    BIO Clinica   24巻2号 Page: 135-140 巻   2009年

  165. 癌に対する抗体療法の現状と展望

    biotherapy   23巻5号 337-45 巻   2009年

  166. 治療抗体作製法

    がん分子標的治療研究実践マニュアル   Page244-249 巻   2009年

  167. 抗CCR4抗体を用いたリンパ腫の治療

    臨床免疫・アレルギー科   52巻1号 :100-110 巻   2009年

  168. 抗CCR4抗体 ~T細胞性腫瘍、そして制御性T細胞~

    血液フロンティア   Vol. 19 No.4 :583-594 巻   2009年

  169. Overexpression of carboxylesterase-2 results in enhanced efficacy of topoisomerase I inhibitor, irinotecan (CPT-11), for multiple myeloma

    YANO Hiroki, KAYUKAWA Satoshi, IIDA Shinsuke, NAKAGAWA Chiharu, OGURI Tetsuya, SANDA Takaomi, DING Jianming, MORI Fumiko, ITO Asahi, RI Masaki, INAGAKI Atsushi, KUSUMOTO Shigeru, ISHIDA Takashi, KOMATSU Hirokazu, INAGAKI Hiroshi, SUZUKI Atsushi, UEDA Ryuzo

    Cancer science   99 巻 ( 11 ) 頁: 2309 - 2314   2008年11月

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    記述言語:英語  

  170. Overexpression of carboxylesterase-2 results in enhanced efficacy of topoisomerase I inhibitor, irinotecan (CPT-11), for multiple myeloma

    Hiroki Yano, Satoshi Kayukawa, Shinsuke Iida, Chiharu Nakagawa, Tetsuya Oguri, Takaomi Sanda, Jianming Ding, Fumiko Mori, Asahi Ito, Masaki Ri, Atsushi Inagaki, Shigeru Kusumoto, Takashi Ishida, Hirokazu Komatsu, Hiroshi Inagaki, Atsushi Suzuki, Ryuzo Ueda

    CANCER SCIENCE   99 巻 ( 11 ) 頁: 2309 - 2314   2008年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Multiple myeloma (MM) remains an incurable disease and further development of novel agents is needed. Because constitutive expression of topoisomerase I (TopoI) in MM cells and the efficacy of SN-38, an active metabolite of irinotecan (CPT-11), have been reported, we investigated the therapeutic potential of CPT-11. Of the eight MM cell lines analyzed, four showed 50% inhibitory concentration values of less than 2 mu g/mL for CPT-11 and less than 2 ng/mL for SN-38. This efficacy was partly explained by the high expression level of human carboxylesterase-2 (hCE-2) in MM cells. Interestingly, high expression of hCE-2 represented the nature of normal plasma cells, suggesting that hCE-2 could efficiently generate SN-38 within the plasma cells. As expected, higher sensitivity to CPT-11 was observed in hCE-2-overexpressing U266 cells than mock U266 cells. On the other hand, the expression levels of hCE-1, TopoI, UGT1A and ABCG2 did not seem to be associated with the sensitivity of MM cells to CPT-11. In a murine xenograft model inoculated s.c. with RPMI8226 cells, administration of CPT-11 alone significantly reduced the tumor volume. When a combination of CPT-11 and bortezomib was administered, the subcutaneous tumors completely disappeared. Thus, clinical trials on CPT-11 in patients with relapsed or refractory MM are warranted. (Cancer Sci 2008; 99: 2309-2314).

    DOI: 10.1111/j.1349-7006.2008.00936.x

    Web of Science

  171. Overexpression of carboxylesterase-2 results in enhanced efficacy of topoisomerase I inhibitor, irinotecan (CPT-11), for multiple myeloma 査読有り

    Hiroki Yano, Satoshi Kayukawa, Shinsuke Iida, Chiharu Nakagawa, Tetsuya Oguri, Takaomi Sanda, Jianming Ding, Fumiko Mori, Asahi Ito, Masaki Ri, Atsushi Inagaki, Shigeru Kusumoto, Takashi Ishida, Hirokazu Komatsu, Hiroshi Inagaki, Atsushi Suzuki, Ryuzo Ueda

    CANCER SCIENCE   99 巻 ( 11 ) 頁: 2309 - 2314   2008年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Multiple myeloma (MM) remains an incurable disease and further development of novel agents is needed. Because constitutive expression of topoisomerase I (TopoI) in MM cells and the efficacy of SN-38, an active metabolite of irinotecan (CPT-11), have been reported, we investigated the therapeutic potential of CPT-11. Of the eight MM cell lines analyzed, four showed 50% inhibitory concentration values of less than 2 mu g/mL for CPT-11 and less than 2 ng/mL for SN-38. This efficacy was partly explained by the high expression level of human carboxylesterase-2 (hCE-2) in MM cells. Interestingly, high expression of hCE-2 represented the nature of normal plasma cells, suggesting that hCE-2 could efficiently generate SN-38 within the plasma cells. As expected, higher sensitivity to CPT-11 was observed in hCE-2-overexpressing U266 cells than mock U266 cells. On the other hand, the expression levels of hCE-1, TopoI, UGT1A and ABCG2 did not seem to be associated with the sensitivity of MM cells to CPT-11. In a murine xenograft model inoculated s.c. with RPMI8226 cells, administration of CPT-11 alone significantly reduced the tumor volume. When a combination of CPT-11 and bortezomib was administered, the subcutaneous tumors completely disappeared. Thus, clinical trials on CPT-11 in patients with relapsed or refractory MM are warranted. (Cancer Sci 2008; 99: 2309-2314).

    DOI: 10.1111/j.1349-7006.2008.00936.x

    Web of Science

  172. 14q32転座関連遺伝子mRNA発現に基づく病型分類は骨髄腫患者の生命予後予測に有用である

    稲垣 淳, 飯田 真介, 森 芙美子, 伊藤 旭, 田島 恵美, 三田 貴臣, 矢野 寛樹, 李 政樹, 粥川 哲, 丁 建民, 楠本 茂, 石田 高司, 花村 一朗, 速水 芳仁, 小松 弘和, 稲垣 宏, 上田 龍三

    臨床血液   49 巻 ( 9 ) 頁: 906 - 906   2008年9月

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    記述言語:日本語   出版者・発行元:(一社)日本血液学会-東京事務局  

  173. Augmentation of antitumour activity of defucosylated chimeric anti-CCR4 monoclonal antibody in SCID mouse model of adult T-cell leukaemia/lymphoma using G-CSF 査読有り

    Hiroki Yano, Takashi Ishida, Kazunori Imada, Tomomi Sakai, Toshihiko Ishii, Atsushi Inagaki, Shinsuke Iida, Takashi Uchiyama, Ryuzo Ueda

    BRITISH JOURNAL OF HAEMATOLOGY   140 巻 ( 5 ) 頁: 586 - 589   2008年3月

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    担当区分:責任著者   記述言語:英語   出版者・発行元:BLACKWELL PUBLISHING  

    DOI: 10.1111/j.1365-2141.2007.06947.x

    Web of Science

  174. ATLに対する抗CCR4抗体の開発

    血液・腫瘍科   56巻5号 Page:562-571 巻   2008年

  175. 免疫調節サイトカインとフコース除去型抗CCR4抗体の併用

    BLOOD TOPICS   VOL3: 30-31 巻   2008年

  176. 抗体による癌の治療

    抗体実験マニュアル   Page236-240 巻   2008年

  177. Defucosylated anti-CC chemokine receptor 4 monoclonal antibody combined with immunomodulatory cytokines: A novel immunotherapy for aggressive/refractory mycosis fungoides and Sezary syndrome

    Hiroki Yano, Takashi Ishida, Atsushi Inagaki, Toshihiko Ishii, Jianmin Ding, Shigeru Kusumoto, Hirokazu Komatsu, Shinsuke Iida, Hiroshi Inagaki, Ryuzo Ueda

    CLINICAL CANCER RESEARCH   13 巻 ( 21 ) 頁: 6494 - 6500   2007年11月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Purpose: Sezary syndrome (SS) and Mycosis fungoides (MF) in the advanced stage have dismal prognoses. Because CC chemokine receptor 4 (CCR4) has an important role in the skin-homing capacity of MF/SS cells, we postulated that anti-CCR4 monoclonal antibody (mAb) could represent a novel therapeutic agent against aggressive/refractory MF/SS.
    Experimental Design: The defucosylated next-generation therapeutic mAb KM2760 induces enhanced antibody-dependent cellular cytotoxicity (ADCC). Here, we assessed the therapeutic potential of this antibody against aggressive MF/SS tumor cells in vitro and in animal models in vivo.
    Results: KM2760 induced robust ADCC by peripheral blood mononuclear cell (PBMC) from healthy controls against a MF/SS cell line as well as against primary tumor cells from patients with aggressive MF/SS. KM2760 also showed significant antitumor activity in disseminated and nondisseminated MF/SS mouse models. In addition, similar to 30% of autologous MF/SS tumor cells were killed in in vitro assays of KM2760-induced ADCC mediated by patients' PBMC after only 4 h, despite the low numbers of natural killer cells present in these PBMCs. It is also shown that ADCC induced by defucosylated therapeutic mAb can be greatly augmented by the immunomodulatory cytokines interleukin-12, IFN-alpha-2b, and IFN-gamma.
    Conclusions: The present study has encouraged us in the conducting of a phase I clinical trial of a completely defucosylated anti-CCR4 mAb in patients with CCR 4-positive T-cell lymphomas, including aggressive MF/SS (ClinicalTrials.gov identifier: NCT00355472). In the near future, the efficacy not only of defucosylated anti-CCR4 mAb single-agent treatment but also of combination therapy with immunomodulatory cytokines will be clinically established to target aggressive/refractory MF/SS.

    DOI: 10.1158/1078-0432.CCR-07-1324

    Web of Science

    PubMed

  178. Clinical significance of a blood eosinophilia in adult T-cell leukemia/lymphoma: A blood eosinophilia is a significant unfavorable prognostic factor 査読有り

    Atae Utsunomiya, Takashi Ishida, Atsushi Inagaki, Toshihiko Ishii, Hiroki Yano, Hirokazu Komatsu, Shinsuke Iida, Kentaro Yonekura, Shogo Takeuchi, Yoshifusa Takatsuka, Ryuzo Ueda

    LEUKEMIA RESEARCH   31 巻 ( 7 ) 頁: 915 - 920   2007年7月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    We investigated the clinical significance of a blood eosinophilia in a cohort of 158 consecutive patients with adult T-cell leukemia/lymphoma (ATLL), and multivariate analysis revealed that a blood eosinophilia was an independent and a significant unfavorable prognostic factor. Interestingly. a blood eosinophilia was independent of serum LDH level, which might reflect the tumor burden. The present study shows that measurement of the blood eosinophil count is useful for predicting the prognosis and for determining a suitable treatment strategy for ATLL patients. (C) 2006 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.leukres.2006.10.017

    Web of Science

  179. Prognostic significance of NPM-ALK fusion transcript overexpression in ALK-positive anaplastic large-cell lymphoma

    Li Chunmei, Takino Hisashi, Eimoto Tadaaki, Ishida Takashi, Inagaki Atsushi, Ueda Ryuzo, Suzuki Ritsuro, Yoshino Tadashi, Nakagawa Atsuko, Nakamura Shigeo, Inagaki Hiroshi

    MODERN PATHOLOGY   20 巻 ( 6 ) 頁: 648 - 655   2007年6月

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    記述言語:日本語  

    Web of Science

  180. Prognostic significance of NPM-ALK fusion transcript overexpression in ALK-positive anaplastic large-cell lymphoma 査読有り

    Chunmei Li, Hisashi Takino, Tadaaki Eimoto, Takashi Ishida, Atsushi Inagaki, Ryuzo Ueda, Ritsuro Suzuki, Tadashi Yoshino, Atsuko Nakagawa, Shigeo Nakamura, Hiroshi Inagaki

    MODERN PATHOLOGY   20 巻 ( 6 ) 頁: 648 - 655   2007年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    In anaplastic large-cell lymphomas positive for anaplastic lymphoma kinase (ALK) protein, the ALK gene is most commonly fused to the NPM gene, and less commonly to TPM3, TFG, ATIC, and other rare genes. Although this lymphoma is generally associated with a favorable clinical outcome, 25% of the patients die of the disease within 5 years. In this study, we developed three assays, all of which can be used with archival formalin-fixed, paraffin-embedded tissues: (1) a sensitive reverse transcription-polymerase chain reaction (RT-PCR) assay for various X-ALK fusion genes, (2) a 50 rapid amplification of cDNA ends (RACE) assay to identify unknown fusion partners, and (3) a real-time RT-PCR assay to quantify the amount of the NPM-ALK fusion transcript. In 26 cases of ALK(+) anaplastic large-cell lymphoma, the RT-PCR assay showed that the ALK was fused to NPM in 21 cases, to TPM3 in three, and to TFG in one. The 50 RACE assay detected ATIC-ALK fusion in the remaining case. The real-time quantitative RT-PCR assay showed that the NPM-ALK transcript was over expressed in four of 20 quantifiable cases. Patients with NPM-ALK overexpression showed a significantly unfavorable overall survival compared with those with a low expression of this transcript. The RT-PCR and 50 RACE assays developed here may be useful for identification of known and unknown gene partners fused to the ALK gene. Overexpression of the NPM-ALK fusion transcript may be associated with a poor prognosis of the patients with ALK(+) anaplastic large-cell lymphomas.

    DOI: 10.1038/modpathol.3800781

    Web of Science

  181. Prognostic significance of NPM-ALK fusion transcript overexpression in ALK-positive anaplastic large-cell lymphoma

    Chunmei Li, Hisashi Takino, Tadaaki Eimoto, Takashi Ishida, Atsushi Inagaki, Ryuzo Ueda, Ritsuro Suzuki, Tadashi Yoshino, Atsuko Nakagawa, Shigeo Nakamura, Hiroshi Inagaki

    MODERN PATHOLOGY   20 巻 ( 6 ) 頁: 648 - 655   2007年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    In anaplastic large-cell lymphomas positive for anaplastic lymphoma kinase (ALK) protein, the ALK gene is most commonly fused to the NPM gene, and less commonly to TPM3, TFG, ATIC, and other rare genes. Although this lymphoma is generally associated with a favorable clinical outcome, 25% of the patients die of the disease within 5 years. In this study, we developed three assays, all of which can be used with archival formalin-fixed, paraffin-embedded tissues: (1) a sensitive reverse transcription-polymerase chain reaction (RT-PCR) assay for various X-ALK fusion genes, (2) a 50 rapid amplification of cDNA ends (RACE) assay to identify unknown fusion partners, and (3) a real-time RT-PCR assay to quantify the amount of the NPM-ALK fusion transcript. In 26 cases of ALK(+) anaplastic large-cell lymphoma, the RT-PCR assay showed that the ALK was fused to NPM in 21 cases, to TPM3 in three, and to TFG in one. The 50 RACE assay detected ATIC-ALK fusion in the remaining case. The real-time quantitative RT-PCR assay showed that the NPM-ALK transcript was over expressed in four of 20 quantifiable cases. Patients with NPM-ALK overexpression showed a significantly unfavorable overall survival compared with those with a low expression of this transcript. The RT-PCR and 50 RACE assays developed here may be useful for identification of known and unknown gene partners fused to the ALK gene. Overexpression of the NPM-ALK fusion transcript may be associated with a poor prognosis of the patients with ALK(+) anaplastic large-cell lymphomas.

    DOI: 10.1038/modpathol.3800781

    Web of Science

  182. [CCR4 as a molecular target for novel immunotherapy in malignant lymphoma].

    Ishida T

    [Rinsho ketsueki] The Japanese journal of clinical hematology   48 巻 ( 4 ) 頁: 262 - 72   2007年4月

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    記述言語:日本語  

    PubMed

  183. CCR4を分子標的とした悪性リンパ腫に対する抗体療法の基礎と応用

    血液フロンティア   Vol. 17 No.12 :1807-1816 巻   2007年

  184. CCR4抗体の開発と臨床

    今日の移植   20巻3号 : 214-225 巻   2007年

  185. CCR4を分子標的とした悪性リンパ腫に対する新規免疫療法

    臨床血液   Vol.48 No.4 262-272 巻   2007年

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  186. 悪性リンパ腫における分子標的としてのCCR4

    血液・腫瘍科   54巻4号 Page408-417 巻   2007年

  187. 造血器腫瘍に対する抗体療法の現状とこれから

    最新医学   62巻6月増刊 巻   2007年

  188. 抗CCR4抗体によるT細胞腫瘍治療

    医学のあゆみ   Vol.220 No.9 797-801 巻   2007年

  189. 抗CCR4抗体

    Pharma Medica   Vol.25 No.3 33-41 巻   2007年

  190. 悪性リンパ腫に対する免疫療法の現状とこれから

    分子細胞治療   Vol. 6 No.6 :525-533 巻   2007年

  191. The CCR4 as a novel-specific molecular target for immunotherapy in Hodgkin lymphoma 査読有り

    T. Ishida, T. Ishii, A. Inagaki, H. Yano, S. Kusumoto, M. Ri, H. Komatsu, S. Iida, H. Inagaki, R. Ueda

    LEUKEMIA   20 巻 ( 12 ) 頁: 2162 - 2168   2006年12月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Here, we report that tumor cells from some patients (23.8%) with Hodgkin lymphoma (HL) are positive for CC chemokine receptor 4 (CCR4). We therefore tested the chimeric anti-CCR4 monoclonal antibody (mAb), KM2760, the Fc region of which is defucosylated to enhance antibody-dependent cellular cytotoxicity (ADCC), as a novel immunotherapy for refractory HL. KM2760 demonstrated a promising antitumor activity in the CCR4-positive HL-bearing mouse model in the therapeutic setting. Although KM2760 did not induce any ADCC mediated by mouse natural killer (NK) cells, it significantly enhanced phagocytosis mediated by mouse monocytes/macrophages against the CCR4-positive HL cell line in vitro. Together with the findings that KM2760 did not exhibit any complement-dependent cytotoxicity or direct antiproliferation activity in vitro, these data indicated that KM2760 exerted its robust in vivo antitumor activity via monocytes/macrophages in mice. In the human system, KM2760 enhanced phagocytic activity mediated by monocytes/macrophages. Furthermore, it induced robust ADCC mediated by NK cells against the CCR4-positive HL cell line in vitro. Thus, it is conceivable that KM2760 would have much more potent antitumor activity in humans than in mice. Collectively, this study strongly indicates that anti-CCR4 mAb could be a novel treatment modality for patients with CCR4-positive HL.

    DOI: 10.1038/sj.leu.2404415

    Web of Science

  192. CCR4 as a novel molecular target for immunotherapy of cancer

    ISHIDA Takashi, UEDA Ryuzo

    Cancer science   97 巻 ( 11 ) 頁: 1139 - 1146   2006年11月

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    記述言語:英語  

  193. CCR4 as a novel molecular target for immunotherapy of cancer 査読有り

    Takashi Ishida, Ryuzo Ueda

    CANCER SCIENCE   97 巻 ( 11 ) 頁: 1139 - 1146   2006年11月

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    記述言語:英語   出版者・発行元:BLACKWELL PUBLISHING  

    Leukocyte trafficking, which is critically regulated by chemokines and their receptors, shares many of the characteristics of tumor cell infiltration and metastasis. Expression of CC chemokine receptor 4 (CCR4) by tumor cells is associated with skin involvement, but CCR4 also has an important role in normal and tumor immunity. In a subset of patients with CCR4(+) T-cell leukemia/lymphoma, the tumor cells themselves function as regulatory T (Treg) cells, contributing to tumor survival in the face of host antitumor immune responses. In other types of cancers, the chemokines TARC/CCL17 and MDC/CCL22, specific ligands for CCR4 that are produced by tumor cells and the tumor microenvironment, attract CCR4(+) Treg cells to the tumor, where they create a favorable environment for tumor escape from host immune responses. A novel humanized anti-CCR4 monoclonal antibody (mAb) has been developed, the Fc region of which is defucosylated to enhance antibody-dependent cellular cytotoxicity by increasing its binding affinity to Fc receptor on effector cells. We are now conducting a phase I clinical trial of this anti-CCR4 mAb in patients with CCR4(+) T-cell leukemia/lymphoma in Japan (clinical trials gov. identifier: NCT00355472). Anti-CCR4 mAb could be an ideal treatment modality for many different cancers, not only to directly kill the CCR4(+) tumor cells, but also to overcome the suppressive effect of CCR4(+) Treg cells on the host immune response to tumor cells.

    DOI: 10.1111/j.1349-7006.200.00307

    Web of Science

  194. CCR4 as a novel molecular target for immunotherapy of cancer

    Takashi Ishida, Ryuzo Ueda

    Cancer Science   97 巻 ( 11 ) 頁: 1139 - 1146   2006年11月

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    記述言語:英語  

    Leukocyte trafficking, which is critically regulated by chemokines and their receptors, shares many of the characteristics of tumor cell infiltration and metastasis. Expression of CC chemokine receptor 4 (CCR4) by tumor cells is associated with skin involvement, but CCR4 also has an important role in normal and tumor immunity. In a subset of patients with CCR4+ T-cell leukemia/lymphoma, the tumor cells themselves function as regulatory T (Treg) cells, contributing to tumor survival in the face of host antitumor immune responses. In other types of cancers, the chemokines TARC/CCL17 and MDC/CCL22, specific ligands for CCR4 that are produced by tumor cells and the tumor microenvironment, attract CCR4+ Treg cells to the tumor, where they create a favorable environment for tumor escape from host immune responses. A novel humanized anti-CCR4 monoclonal antibody (mAb) has been developed, the Fc region of which is defucosylated to enhance antibody-dependent cellular cytotoxicity by increasing its binding affinity to Fc receptor on effector cells. We are now conducting a phase I clinical trial of this anti-CCR4 mAb in patients with CCR4+ T-cell leukemia/lymphoma in Japan (clinical trials gov. identifier: NCT00355472). Anti-CCR4 mAb could be an ideal treatment modality for many different cancers, not only to directly kill the CCR4+ tumor cells, but also to overcome the suppressive effect of CCR4+ Treg cells on the host immune response to tumor cells. © 2006 Japanese Cancer Association.

    DOI: 10.1111/j.1349-7006.2006.00307.x

    Scopus

    PubMed

  195. Measurement of atmospheric neutrino flux consistent with tau neutrino appearance

    Abe K., Hayato Y., Iida T., Ishihara K., Kameda J., Koshio Y., Minamino A., Mitsuda C., Miura M., Moriyama S., Nakahata M., Obayashi Y., Ogawa H., Shiozawa M., Suzuki Y., Takeda A., Takeuchi Y., Ueshima K., Higuchi I., Ishihara C., Ishitsuka M., Kajita T., Kaneyuki K., Mitsuka G., Nakayama S., Nishino H., Okumura K., Saji C., Takenaga Y., Totsuka Y., Clark S., Desai S., Dufour F., Kearns E., Likhoded S., Litos M., Raaf J. L., Stone J. L., Sulak L. R., Wang W., Goldhaber M., Casper D., Cravens J. P., Kropp W. R., Liu D. W., Mine S., Regis C., Smy M. B., Sobel H. W., Vagins M. R., Ganezer K. S., Hill J. E., Keig W. E., Jang J. S., Kim J. Y., Lim I. T., Scholberg K., Tanimoto N., Walter C. W., Wendell R., Ellsworth R. W., Tasaka S., Guillian E., Learned J. G., Matsuno S., Messier M. D., Ichikawa A. K., Ishida T., Ishii T., Iwashita T., Kobayashi T., Nakadaira T., Nakamura K., Nitta K., Oyama Y., Suzuki A. T., Hasegawa M., Kato I., Maesaka H., Nakaya T., Nishikawa K., Sasaki T., Sato H., Yamamoto S., Yokoyama M., Haines T. J., Dazeley S., Hatakeyama S., Svoboda R., Sullivan G. W., Habig A., Gran R., Fukuda Y., Sato T., Itow Y., Koike T., Jung C. K., Kato T., Kobayashi K., Malek M., McGrew C., Sarrat A., Terri R., Yanagisawa C., Tamura N., Sakuda M., Sugihara M., Kuno Y., Yoshida M., Kim S. B., Yoo J., Ishizuka T., Okazawa H., Choi Y., Seo H. K., Gando Y., Hasegawa T., Inoue K., Ishii H., Nishijima K., Ishino H., Watanabe Y., Koshiba M., Kielczewska D., Zalipska J., Berns H. G., Shiraishi K. K., Washburn K., Wilkes R. J.

    PHYSICAL REVIEW LETTERS   97 巻 ( 17 )   2006年10月

     詳細を見る

    記述言語:日本語  

    DOI: 10.1103/PhysRevLett.97.171801

    Web of Science

  196. Clinical significance of serum Th1-, Th2-and regulatory T cells-associated cytokines in adult T-cell leukemia/lymphoma: High Interleukin-5 and -10 levels are significant unfavorable prognostic factors

    A Inagaki, T Ishida, T Ishii, H Komatsu, S Iida, JM Ding, K Yonekura, S Takeuchi, Y Takatsuka, A Utsunomiya, R Ueda

    INTERNATIONAL JOURNAL OF CANCER   118 巻 ( 12 ) 頁: 3054 - 3061   2006年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Patients with adult T-cell leukemia/lyphoma (ATLL) are in a severely immunocompromised state. therefore, it is assumed that ATLL cells either express particular cytokines or induce their expression in host immune cells, disrupting the balanced production of cytokines and causing the host's immune system to break down. We examined the levels of serum cytokines including T helper type 1- (Th1-) associated cytokines [IFN-gamma, TNF-alpha, and interleukin (IL)-2], Th2-associated cytokines (IL-4, -5 and -6) and regulatory T cell-associated cytokines (IL-10 and TGF-beta 1) in 94 ATLL patients, 39 asymptomatic human T-cell lymphotropic -virus type-1 (HTLV-1) carriers and 50 healthy adult volunteers, to clarify whether elevated levels of particular cytokines are associated with the prognosis of ATLL patients. On multivariate analysis, high IL-5 and IL-10 levels were independent and significant unfavorable prognostic factors among the ATLL patients. The IL-10 level significantly increased with disease progression at each step from asymptomatic HTLV-I carrier to ATLL of the indolent variant (chronic and smoldering subtypes) to ATLL of the aggressive variant (acute and lymphoma subtypes). Furthermore, high IL-10 was significantly associated with high lactate dehydrogenase (LDH), indicating that the IL-10 level reflects the tumor burden. The IL-5 level was not associated with disease progression nor LDH. Among ATLL patients with the aggressive variant, high IL-5, but not high IL-10, was an independent and significant unfavorable prognostic factor on multivariate analysis. Measurement of serum IL-5 and IL-10 levels is useful for predicting the prognosis and for determining a suitable treatment strategy for ATLL patients. (c) 2006 Wiley-Liss, Inc.

    DOI: 10.1002/ijc.21688

    Web of Science

  197. "抗CCR4抗体 ベンチからベッドサイドへ"

    "医学のあゆみ"   219 巻 ( 1 ) 頁: 51 - 56   2006年

  198. 造血器腫瘍に対する抗体療法

    現代医学   Vol.54 No.2 285-293, 巻   2006年

  199. Anti-myeloma effects of a novel synthetic retinoid Am80 (Tamibarotene) through inhibition of angiogenesis.

    T Sanda, S Iida, T Kuwano, M Ono, R Ueda

    BLOOD   106 巻 ( 11 ) 頁: 364B - 364B   2005年11月

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    記述言語:英語   出版者・発行元:AMER SOC HEMATOLOGY  

    DOI: 10.1038/sj.leu.2403754

    Web of Science

  200. Clinical significance of serum Th1-, Th2- and regulatory T cells-associated cytokines in adult T-cell leukemia/lymphoma: High interleukin-5 and-10 levels are significant unfavorable prognostic factors 査読有り

    A Inagaki, T Ishida, T Ishii, H Komatsu, S Iida, K Yonekura, S Takeuchi, Y Takatsuka, A Utsunomiya, R Ueda

    BLOOD   106 巻 ( 11 ) 頁: 793A - 793A   2005年11月

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    記述言語:英語   出版者・発行元:AMER SOC HEMATOLOGY  

    DOI: 10.1002/ijc.21688

    Web of Science

  201. CC chemokine receptor 4-positive diffuse large B-cell lymphoma involving the skin: A case report 査読有り

    T Ishida, H Inagaki, S Kusumoto, A Inagaki, H Komatsu, S Iida, S Harada, G Takeuchi, R Ueda

    INTERNATIONAL JOURNAL OF HEMATOLOGY   82 巻 ( 2 ) 頁: 148 - 151   2005年8月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CARDEN JENNINGS PUBL CO LTD  

    Leukocyte trafficking is critically regulated by chemokines and their receptors. The involvement of the skin in certain subsets of T-cell malignancies has been explained by the discovery of an interaction between the thymus and activation-regulated chemokine (TARC), which is abundant in the skin, and its receptor, CC chemokine receptor 4 (CCR4), which is expressed in the tumor cells. We describe a diffuse large B-cell lymphoma (DLBCL) that showed CCR4 expression with involvement of the skin. A 55-year-old man presented with a giant skin ulcer of the right axilla, and his disease was diagnosed as DLBCL. Further clinical examination revealed an ulcerated gastric lymphoma lesion. Immunohistochemical and real-time reverse transcriptase-polymerase chain reaction analyses showed that the tumor cells were positive for CCR4, and TARC was expressed at extremely high levels in the lymphoma-affected skin. These observations suggest that the interaction between CCR4 and TARC played a significant role in the involvement of the skin in this case, similar to what has been observed in certain subsets of T-cell malignancies. To the best of our knowledge, this report is the first of a CCR4-positive B-cell lymphoma. The present case provides new insights into the pathogenesis of skin involvement in B-cell lymphomas.

    DOI: 10.1532/IJH97.04154

    Web of Science

    PubMed

  202. Diffuse large B-cell lymphoma with extra Bcl-2 gene signals detected by FISH analysis is associated with a "non-Germinal center phenotype" 査読有り

    S Kusumoto, Y Kobayashi, N Sekiguchi, K Tanimoto, Y Onishi, Y Yokota, T Watanabe, AM Maeshima, T Ishida, H Inagaki, Y Matsuno, R Ueda, K Tobinai

    AMERICAN JOURNAL OF SURGICAL PATHOLOGY   29 巻 ( 8 ) 頁: 1067 - 1073   2005年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Amplification and translocation of the Bcl-2 gene has been detected in a certain subset of diffuse large B-cell lymphomas (DLBCL). The correlations among Bcl-2 protein expression, gene translocation or amplification, and the molecular signature determined by cDNA array are poorly understood. This Study examined 25 cases with de novo nodal DLBCL. Interphase fluorescence in situ hybridization (FISH) analysis was performed to evaluate the Bcl-2 gene using IGH/BCL2 and CEP18 centrornere probes (Vysis). When extra Bcl-2 gene signals were observed in each tumor cell and when these signals were in proportion to the extra CEP 18 probe signals, we regarded the findings as indicating the presence of an additional chromosome 18; when extra Bcl-2 signals were observed but additional CEP18 signals were not, we regarded the findings as indicating the presence of gene amplification. A panel of 3 antigens (CD 10, Bcl-6, and MUM-1) was applied to categorize each case as either a "germinal center B-cell (GCB) phenotype" or a "non-GCB phenotype." Of the 25 cases examined, 8 cases (32%) were classified as "GCB phenotype" and 17 cases (68%) were classified as "non-GCB phenotype." A FISH analysis revealed that t(14;18) was detected in 2 of the 8 cases (25%) with the "GCB phenotype" but in none of the 17 "non-GCB phenotype" cases. Extra Bcl-2 gene signals were detected in 7 of the 25 (28%) cases examined: n = 5 for an additional chromosome 18, n I for gene amplification, and n = I for additional chromosome 18 + gene amplification. Extra Bcl-2 gene signals were exclusively detected in DLBCL with the "non-GCB phenotype"; these cases, with the exception of one, stained strongly positive for Bcl-2. The DLBCLs with Bcl-2 protein overexpression were classified into at least two heterogeneous Molecular groups, based on the results of the FISH analysis.

    Web of Science

  203. Multiple myeloma oncogene 1 (MUM1)/interferon regulatory factor 4 (IRF4) upregulates monokine induced by interferon-gamma (MIG) gene expression in B-cell malignancy 査読有り

    M Uranishi, S Iida, T Sanda, T Ishida, E Tajima, M Ito, H Komatsu, H Inagaki, R Ueda

    LEUKEMIA   19 巻 ( 8 ) 頁: 1471 - 1478   2005年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    MUM1 ( multiple myeloma oncogene 1)/IRF4 ( interferon regulatory factor 4) is a transcription factor that is activated as a result of t(6;14)(p25;q32) in multiple myeloma. MUM1 expression is seen in various B-cell lymphomas and predicts an unfavorable outcome in some lymphoma subtypes. To elucidate its role in B-cell malignancies, we prepared MUM1-expressing Ba/F3 cells, which proliferated until higher cellular density than the parental cells, and performed cDNA microarray analysis to identify genes whose expression is regulated by MUM1. We found that the expression of four genes including FK506-binding protein 3 (FKBP3), the monokine induced by interferon-gamma(MIG), Fas apoptotic inhibitory molecule (Faim) and Zinc-finger protein 94 was altered in the MUM1-expressing cells. We then focused on MIG since its expression was immediately upregulated by MUM1. In reporter assays, MUM1 activated the MIG promoter in cooperation with PU.1, and the interaction between MUM1 and the MIG promoter sequence was confirmed. The expression of MIG was correlated with that of MUM1 in B-CLL cell lines, and treatment with neutralizing antibodies against MIG and its receptor, CXCR3, slightly inhibited the proliferation of two MUM1-expressing lines. These results suggest that MUM1 plays roles in the progression of B-cell lymphoma/leukemia by regulating the expression of various genes including MIG.

    DOI: 10.1038/sj.leu.2403833

    Web of Science

  204. Multiple myeloma oncogene 1 (MUM1)/interferon regulatory factor 4 (IRF4) upregulates monokine induced by interferon-gamma (MIG) gene expression in B-cell malignancy

    M Uranishi, S Iida, T Sanda, T Ishida, E Tajima, M Ito, H Komatsu, H Inagaki, R Ueda

    LEUKEMIA   19 巻 ( 8 ) 頁: 1471 - 1478   2005年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    MUM1 ( multiple myeloma oncogene 1)/IRF4 ( interferon regulatory factor 4) is a transcription factor that is activated as a result of t(6;14)(p25;q32) in multiple myeloma. MUM1 expression is seen in various B-cell lymphomas and predicts an unfavorable outcome in some lymphoma subtypes. To elucidate its role in B-cell malignancies, we prepared MUM1-expressing Ba/F3 cells, which proliferated until higher cellular density than the parental cells, and performed cDNA microarray analysis to identify genes whose expression is regulated by MUM1. We found that the expression of four genes including FK506-binding protein 3 (FKBP3), the monokine induced by interferon-gamma(MIG), Fas apoptotic inhibitory molecule (Faim) and Zinc-finger protein 94 was altered in the MUM1-expressing cells. We then focused on MIG since its expression was immediately upregulated by MUM1. In reporter assays, MUM1 activated the MIG promoter in cooperation with PU.1, and the interaction between MUM1 and the MIG promoter sequence was confirmed. The expression of MIG was correlated with that of MUM1 in B-CLL cell lines, and treatment with neutralizing antibodies against MIG and its receptor, CXCR3, slightly inhibited the proliferation of two MUM1-expressing lines. These results suggest that MUM1 plays roles in the progression of B-cell lymphoma/leukemia by regulating the expression of various genes including MIG.

    DOI: 10.1038/sj.leu.2403833

    Web of Science

  205. Diffuse large B-cell lymphoma with extra Bcl-2 gene signals detected by FISH analysis is associated with a "non-germinal center phenotype".

    Kusumoto S, Kobayashi Y, Sekiguchi N, Tanimoto K, Onishi Y, Yokota Y, Watanabe T, Maeshima AM, Ishida T, Inagaki H, Matsuno Y, Ueda R, Tobinai K

    The American journal of surgical pathology   29 巻 ( 8 ) 頁: 1067 - 73   2005年8月

     詳細を見る

    記述言語:英語  

    PubMed

  206. Diffuse large B-cell lymphoma with extra Bcl-2 gene signals detected by FISH analysis is associated with a "non-germinal center phenotype"

    Kusumoto S., Kobayashi Y., Sekiguchi N., Tanimoto K., Onishi Y., Yokota Y., Watanabe T., Maeshima A.M., Ishida T., Inagaki H., Matsuno Y., Ueda R., Tobinai K.

    American Journal of Surgical Pathology   29 巻 ( 8 ) 頁: 1067 - 1073   2005年8月

     詳細を見る

    記述言語:日本語   出版者・発行元:American Journal of Surgical Pathology  

    Amplification and translocation of the Bcl-2 gene has been detected in a certain subset of diffuse large B-cell lymphomas (DLBCL). The correlations among Bcl-2 protein expression, gene translocation or amplification, and the molecular signature determined by cDNA array are poorly understood. This study examined 25 cases with de novo nodal DLBCL. Interphase fluorescence in situ hybridization (FISH) analysis was performed to evaluate the Bcl-2 gene using IGH/BCL2 and CEP18 centromere probes (Vysis). When extra Bcl-2 gene signals were observed in each tumor cell and when these signals were in proportion to the extra CEP18 probe signals, we regarded the findings as indicating the presence of an additional chromosome 18; when extra Bcl-2 signals were observed but additional CEP18 signals were not, we regarded the findings as indicating the presence of gene amplification. A panel of 3 antigens (CD10, Bcl-6, and MUM-1) was applied to categorize each case as either a "germinal center B-cell (GCB) phenotype" or a "non-GCB phenotype." Of the 25 cases examined, 8 cases (32%) were classified as "GCB phenotype" and 17 cases (68%) were classified as "non-GCB phenotype." A FISH analysis revealed that t(14;18) was detected in 2 of the 8 cases (25%) with the "GCB phenotype" but in none of the 17 "non-GCB phenotype" cases. Extra Bcl-2 gene signals were detected in 7 of the 25 (28%) cases examined: n = 5 for an additional chromosome 18, n = 1 for gene amplification, and n = 1 for additional chromosome 18 + gene amplification. Extra Bcl-2 gene signals were exclusively detected in DLBCL with the "non-GCB phenotype"; these cases, with the exception of one, stained strongly positive for Bcl-2. The DLBCLs with Bcl-2 protein over-expression were classified into at least two heterogeneous molecular groups, based on the results of the FISH analysis. Copyright © 2005 by Lippincott Williams & Wilkins.

    Scopus

  207. Antimyeloma effects of a novel synthetic retinoid Am80 (Tamibarotene) through inhibition of angiogenesis 査読有り

    T Sanda, T Kuwano, S Nakao, S Iida, T Ishida, H Komatsu, K Shudo, M Kuwano, M Ono, R Ueda

    LEUKEMIA   19 巻 ( 6 ) 頁: 901 - 909   2005年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    In multiple myeloma ( MM), the interaction between myeloma cells and bone marrow microenvironment has an important role in the pathogenesis of MM. We first examined the inducing effect of myeloma cells on migration of human umbilical vein vascular endothelial cells ( HUVECs). Five myeloma cell lines produced varying amounts of VEGF, and migration of HUVECs was induced by coculture with myeloma cells. We next examined the inhibitory effect of a novel synthetic retinoid Am80 ( Tamibarotene) on both myeloma cells and HUVECs. Am80 is specific for the retinoic- acid receptor- alpha/beta, and has therapeutic effects in all- trans retinoic acid resistant acute promyelocytic leukemia. Am80 slightly inhibited the growth of both myeloma cells and HUVECs, and remarkably inhibited the growth of HUVECs stimulated by VEGF. Am80 showed little growth inhibition of bone marrow stromal cells ( BMSCs), but it markedly inhibited migration of HUVECs by cocultured myeloma cells. Am80 inhibited VEGF- induced phosphorylation of VEGF receptor. In addition, VEGF- induced formation of tubelike structures in vitro and neovascularization in mouse corneas were significantly inhibited by Am80. These findings clearly demonstrate that Am80 is a potential inhibitor of angiogenesis caused by the interaction between vascular endothelial cells and myeloma cells, and might be a useful therapeutic agent against MM.

    DOI: 10.1038/sj.leu.2403754

    Web of Science

  208. "CCR4を分子標的とした難治性T細胞性腫瘍に対する新規抗体療法"

    "血液・腫瘍科"   50 巻 ( 4 ) 頁: 418 - 427   2005年

  209. "CCR4を分子標的とする難治性T細胞性腫瘍に対する新規抗体療法"

    "別冊・医学のあゆみ 血液疾患- state of arts Ver.3"     頁: 5 - 458   2005年

  210. "CCR4を分子標的とするT細胞性腫瘍に対する新規免疫療法"

    "医学のあゆみ"   212 巻 ( 4 ) 頁: 281 - 282   2005年

  211. "Adult T-cell leukemia/lymphoma(ATLL)におけるケモカイン受容体発現の臨床的意義"

    "血液・腫瘍科"   49 巻 ( 3 ) 頁: 240 - 249   2004年

  212. "抗体療法の更なる展開"

    Medical Science Digest   30 巻 ( 4 ) 頁: 138 - 142   2004年

  213. Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome.

    Ishida T, Utsunomiya A, Iida S, Inagaki H, Takatsuka Y, Kusumoto S, Takeuchi G, Shimizu S, Ito M, Komatsu H, Wakita A, Eimoto T, Matsushima K, Ueda R

    Clinical cancer research : an official journal of the American Association for Cancer Research   9 巻 ( 10 Pt 1 ) 頁: 3625 - 34   2003年9月

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    記述言語:英語  

    PubMed

  214. 成人T細胞白血病リンパ腫におけるCCR4発現の意義

    石田 高司, 飯田 真介, 稲垣 宏, 楠本 茂, 三田 貴臣, 稲垣 淳, 粥川 哲, 加藤 美幸, 花村 一朗, 伊藤 公人, 清水 重喜, 小松 弘和, 脇田 充史, 竹内 元二, 栄本 忠昭, 上田 龍三

    名古屋市立大学医学会雑誌   54 巻 ( 2〜3 ) 頁: 113 - 113   2003年8月

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    記述言語:日本語   出版者・発行元:名古屋市立大学医学会  

  215. 多発性骨髄腫転座関連遺伝子MUM1のB細胞性腫瘍における標的遺伝子の検討

    加藤 美幸, 飯田 真介, 粥川 哲, 石田 高司, 花村 一朗, 速水 芳仁, 小松 弘和, 脇田 充史, 上田 龍三

    日本癌学会総会記事   62回 巻   頁: 182 - 182   2003年8月

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    記述言語:日本語   出版者・発行元:日本癌学会  

  216. Frequent occurrence of CCND1 deregulation in patients with early stages of plasma cell dyscrasia

    MIURA Kazuhisa, IIDA Shinsuke, HANAMURA Ichiro, KATO Miyuki, BANNO Shogo, ISHIDA Takashi, KUSUMOTO Shigeru, TAKEUCHI Genji, MIWA Hiroshi, NITTA Masakazu, INAGAKI Hiroshi, EIMOTO Tadaaki, NOMURA Kenichi, TANIWAKI Masafumi, UEDA Ryuzo

    Cancer science   94 巻 ( 4 ) 頁: 350 - 354   2003年4月

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    記述言語:英語  

  217. Frequent occurrence of CCND1 deregulation in patients with early stages of plasma cell dyscrasia 査読有り

    K Miura, S Iida, Hanamura, I, M Kato, S Banno, T Ishida, S Kusumoto, G Takeuchi, H Miwa, M Nitta, H Inagaki, T Eimoto, K Nomura, M Taniwaki, R Ueda

    CANCER SCIENCE   94 巻 ( 4 ) 頁: 350 - 354   2003年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JAPANESE CANCER ASSOC  

    Chromosomal translocations involving the immunoglobulin heavy chain gene (IgH) and nonrandom protooncogene loci are the hallmark of genetic alterations found not only in multiple myeloma (MM), but also in premalignant stages of MM, including monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). We studied the frequency of IgH (14q32) rearrangements and their partner chromosomes in 16 Japanese patients with MGUS (13 cases), and SMM (3 cases) by means of interphase double-color fluorescence in situ hybridization (DCFISH) applied to purified plasma cells and using CD138-bead selection. IgH rearrangement was recognized in nine of the patients (56.3%). Protooncogene loci juxtaposed to IgH were identified in seven cases including CCND1 (11q13) in six cases and FGFR3 (4p16) in one. Four out of the six t(11;14)-positive cases showed nuclear staining of the cyclin D1 protein, whereas none of the seven t(11;14)-negative cases did. Moreover, neither MUM1(6p25)-IgH nor MAFB(20q11)-IgH fusion signals were observed. This suggests to us that cyclin D1 deregulation due to the presence of t(11;14) is involved in the early development of plasma cell neoplasms, and that this event alone is not enough for the development of symptomatic myeloma.

    DOI: 10.1111/j.1349-7006.2003.tb01445.x

    Web of Science

  218. Clinical Significance of CCR4 Expression in Adult T-Cell Leukemia/Lymphoma: Its Close Association with Skin Involvement and Unfavorable Outcome

    Ishida T., Utsunomiya A., Iida S., Inagaki H., Takatsuka Y., Kusumoto S., Takeuchi G., Shimizu S., Ito M., Komatsu H., Wakita A., Eimoto T., Matsushima K., Ueda R.

    Clinical Cancer Research   9 巻 ( 10 ) 頁: 3625 - 3634   2003年

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    記述言語:日本語   出版者・発行元:Clinical Cancer Research  

    Adult T-cell leukemia/lymphoma (ATLL) is a distinct clinical entity among mature T-cell neoplasms, and its causative agent has been confirmed to be long-term infection by human T-lymphotropic virus type 1. A recent study demonstrated frequent expression of a chemokine receptor, CC chemokine receptor (CCR)4, which is known as a Th2 marker but not CXC chemokine receptor (CXCR)3, which is known as a Th1 marker, among both ATLL- and human T-lymphotropic virus type 1-immortalized T cells. In this study, immunostaining analysis for CCR4 and CXCR3 expression in ATLL cells obtained from 103 patients with ATLL was performed, and the clinical parameters and overall survival of the CCR4-positive and -negative cases were compared. Ninety-one (88.3%) of the 103 cases were positive for CCR4 staining, whereas only 5 (4.9%) were positive for CXCR3 staining. Positivity for CCR4 was significantly associated with skin involvement (P < 0.05), although there were no significant differences in clinical characteristics between the CCR4-positive and -negative cases at the time of initial diagnosis. CCR4+ ATLL cells may accumulate in the skin because of the expression of a CCR4 ligand, thymus and activation-regulated chemokine (TARC), on normal and inflamed cutaneous endothelia. As for survival analysis, positivity for CCR4 expression was extracted as an unfavorable prognostic factor as well as other factors, including the presence of B symptoms and extranodal involvement of more than one site. Multivariate analysis confirmed that CCR4 expression was an independent and significant prognostic factor (P <0.05). Thus, our finding may provide a novel insight into not only the biological but also the clinical features of ATLL. © 2003, American Association for Cancer Research. All rights reserved.

    Scopus

  219. 成人T細胞白血病リンパ腫におけるCCR4発現の臨床的意義(Clinical Significance of The CCR4 expression in Adult T-cell Leukemia/Lymphoma(ATLL): Its Close Association with Skin Involvement And Unfavorable Outcome)

    石田 高司, 宇都宮 與, 飯田 真介, 稲垣 宏, 清水 重喜, 小松 弘和, 伊藤 公人, 花村 一朗, 速水 芳人, 加藤 美幸, 脇田 充史, 上田 龍三

    日本癌学会総会記事   61回 巻   頁: 392 - 392   2002年10月

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    記述言語:英語   出版者・発行元:日本癌学会  

  220. 多発性骨髄腫細胞における転座関連原癌遺伝子発現の定量解析

    加藤 美幸, 小松 弘和, 石田 高司, 花村 一朗, 速水 芳人, 伊藤 公人, 飯田 真介, 脇田 充史, 上田 龍三

    日本癌学会総会記事   61回 巻   頁: 394 - 394   2002年10月

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    記述言語:日本語   出版者・発行元:日本癌学会  

  221. 再発・難治性peripheral T-cell lymphomaに対する同種造血幹細胞移植2例の検討

    石田 高司, 飯田 真介, 粥川 哲, 加藤 美幸, 花村 一朗, 速水 芳人, 三浦 和久, 伊藤 公人, 小松 弘和, 坂野 章吾, 上田 龍三, 脇田 充史

    臨床血液   43 巻 ( 9 ) 頁: 886 - 887   2002年9月

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    記述言語:日本語   出版者・発行元:(一社)日本血液学会-東京事務局  

  222. 早期plasma cell dyscrasiaの発症に関与する14q32の同定

    三浦 和久, 飯田 真介, 花村 一朗, 稲垣 宏, 野村 憲一, 石田 高司, 小松 弘和, 坂野 章吾, 脇田 充史, 楠本 茂, 竹内 元二, 三輪 啓志, 仁田 正和, 谷脇 雅史, 上田 龍三

    臨床血液   43 巻 ( 8 ) 頁: 187 - 187   2002年8月

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    記述言語:日本語   出版者・発行元:(一社)日本血液学会-東京事務局  

  223. CD10+,CD25+であったHairy cell leukemia variantの1例

    速水 芳仁, 粥川 哲, 石田 高司, 加藤 美幸, 花村 一朗, 伊藤 公人, 小松 弘和, 飯田 真介, 脇田 充史, 上田 龍三

    臨床血液   43 巻 ( 8 ) 頁: 462 - 462   2002年8月

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    記述言語:日本語   出版者・発行元:(一社)日本血液学会-東京事務局  

  224. 成人T細胞白血病リンパ腫におけるCCR4発現の意義

    石田 高司, 宇都宮 與, 飯田 真介, 稲垣 宏, 高塚 祥芝, 楠本 茂, 加藤 美幸, 花村 一朗, 速水 芳人, 伊藤 公人, 小松 弘和, 坂野 章吾, 脇田 充史, 竹内 元二, 上田 龍三

    臨床血液   43 巻 ( 8 ) 頁: 87 - 87   2002年8月

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    記述言語:日本語   出版者・発行元:(一社)日本血液学会-東京事務局  

  225. Successful treatment of nasal T-cell lymphoma with a combination of local irradiation and high-dose chemotherapy 査読有り

    T Sanda, S Iida, M Ito, K Tsuboi, K Miura, S Harada, H Komatsu, A Wakita, H Inagaki, R Ueda

    INTERNATIONAL JOURNAL OF HEMATOLOGY   75 巻 ( 2 ) 頁: 195 - 200   2002年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CARDEN JENNINGS PUBL CO LTD  

    Nasal natural killer (NK)/T-cell lymphoma is characterized by an aggressive clinical course and poor prognosis. The term "NK/T-cell" lymphoma includes both the NK-cell type and the T-cell type, which are classified by immunophenotyping and according to T-cell receptor (TCR) rearrangement. In addition, CD56(+)T-cell lymphoma is defined as NK-like T-cell lymphoma. This report concerns a 54-year-old woman with nasal T-cell lymphoma. Its phenotype showed pure T-cell type with CD3(+), CD56(-), and TCR+ accompanied by Epstein-Barr virus infection. Although the lesions were localized in the nasal mucosa and facial skin (stage IE), local irradiation could not achieve complete remission (CR). We then administered 5 courses of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) regimen followed by high-dose chemotherapy with an autologous peripheral blood stem cell transplantation. This therapy resulted in CR. Our results suggest that this lymphoma subtype may be cured by means of intensive treatment soon after diagnosis. Int J Hematol. 2002;75:195-200. (C)2002 The Japanese Society of Hematology.

    Web of Science

  226. CLLにおけるMUM1発現の意義

    伊藤 公人, 飯田 真介, 坪井 一哉, 稲垣 宏, 石田 高司, 加藤 美幸, 速水 芳仁, 花村 一朗, 三浦 和久, 脇田 充史

    名古屋市立大学医学会雑誌   52 巻 ( 4 ) 頁: 261 - 261   2001年11月

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    記述言語:日本語   出版者・発行元:名古屋市立大学医学会  

  227. cisplatin+vinorelbineを用いた肺扁平上皮癌の治療後に発症した,inv(16)を有する急性単球性白血病

    原田 信助, 飯田 真介, 石田 高司, 加藤 美幸, 速水 芳仁, 花村 一朗, 三浦 和久, 伊藤 公人, 小松 弘和, 坂野 章吾

    臨床血液   42 巻 ( 10 ) 頁: 1024 - 1024   2001年10月

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    記述言語:日本語   出版者・発行元:(一社)日本血液学会-東京事務局  

  228. "Nucleic Acid Amplification Testにより発見された輸血後B型肝炎の1例"

    "日本輸血学会雑誌"   46 巻   頁: 449 - 453   2000年

▼全件表示

MISC 53

  1. Quantitatively immunological characterization of mogamulizumab skin disorders in ATL patients 査読有り

    Asahi Ito, Yui Suzuki, Ayako Masaki, Shinichiro Yoshida, Hitoshi Suzushima, Shigeki Takemoto, Atae Utsunomiya, Toshihiko Ishii, Masanori Hiura, Takeshi Takahashi, Satoshi Yurimoto, Hiroshi Inagaki, Akimichi Morita, Shinsuke Iida, Takashi Ishida  

    J Cutan Immunol Allergy. ( 2 ) 頁: 102-107   2019年

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  2. モガムリズマブ、ニボルマブ二剤併用術前免疫療法第I相医師主導治験において得られた免疫組織染色結果の暫定的報告(Interim immunostaining results from phase I study of pre-operative combination therapy with mogamulizumab and nivolumab)

    鈴木 進, 都築 豊徳, 石田 高司, 小島 隆嗣, 垣見 和宏, 飯田 真介, 岡 三喜男, 土岐 祐一郎, 西川 博嘉, 上田 龍三, 和田 尚  

    日本癌学会総会記事77回 巻   頁: 105 - 105   2018年9月

     詳細を見る

    記述言語:英語   出版者・発行元:日本癌学会  

  3. ATLに対するTax標的樹状細胞ワクチン療法 第Ia/Ib相医師主導治験(Tax targeting dendritic cell vaccine for ATL: A phase Ia/Ib clinical study)

    末廣 陽子, 福田 哲也, 白土 基明, 飯野 忠史, 長谷川 温彦, 安永 純一朗, 平田 明恵, 宇都宮 勇人, 大野 博文, 石田 高司, 赤司 浩一, 松岡 雅雄, 神奈木 真理  

    臨床血液59 巻 ( 9 ) 頁: 1518 - 1518   2018年9月

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    記述言語:英語   出版者・発行元:(一社)日本血液学会-東京事務局  

  4. 愛知県の12基幹病院における輸血医療のインシデント・アクシデントに関する実態調査

    永田 梨奈, 松浦 秀哲, 杉浦 縁, 石田 高司, 大西 一功, 小澤 幸泰, 笠井 雅信, 加藤 栄史, 木下 朝博, 河野 彰夫, 近藤 勝, 齋藤 俊樹, 澤 正史, 杉浦 勇, 松下 正, 赤塚 美樹, 愛知県合同輸血療法委員会  

    日本輸血細胞治療学会誌64 巻 ( 2 ) 頁: 324 - 324   2018年4月

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    記述言語:日本語   出版者・発行元:(一社)日本輸血・細胞治療学会  

  5. 生検後に自然消退を認めたびまん性大細胞型B細胞リンパ腫の1例

    小林 由佳, 加藤 裕史, 森田 明理, 小芦 雄介, 石田 高司  

    日本皮膚科学会雑誌128 巻 ( 1 ) 頁: 79 - 79   2018年1月

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    記述言語:日本語   出版者・発行元:(公社)日本皮膚科学会  

  6. Aggressive成人T細胞白血病リンパ腫(ATL)患者に対する同種造血幹細胞移植前・後のモガムリズマブの使用に関する合意形成会議 : 適切な使用にむけて

    宇都宮 與, 石田 高司, 石塚 賢治, 加藤 光次, 崔 日承, 中野 伸亮, 藤 重夫, 松岡 賢市  

    血液内科 = Hematology75 巻 ( 4 ) 頁: 544 - 550   2017年10月

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    記述言語:日本語   出版者・発行元:科学評論社  

    CiNii Books

  7. 抗CCR4抗体 モガムリズマブ (特集 がん分子標的薬の効果と副作用 : 期待される効果と評価) -- (抗体薬)

    伊藤 旭, 石田 高司  

    日本臨床 = Japanese journal of clinical medicine75 巻 ( 9 ) 頁: 1347 - 1352   2017年9月

     詳細を見る

    記述言語:日本語   出版者・発行元:日本臨床社  

    CiNii Books

    その他リンク: http://search.jamas.or.jp/link/ui/2017341879

  8. 【免疫療法の進歩と問題点】Tregを標的としたがん免疫治療

    浦川 真哉, 土岐 祐一郎, 小島 隆嗣, 鈴木 進, 石田 高司, 西川 博嘉, 垣見 和宏, 飯田 真介, 岡 三喜男, 中山 睿一, 上田 龍三, 和田 尚  

    腫瘍内科20 巻 ( 2 ) 頁: 137 - 142   2017年8月

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    記述言語:日本語   出版者・発行元:(有)科学評論社  

    J-GLOBAL

  9. Identification of Super-Enhancer-Associated Cancer Genes Provides Novel Therapeutic Targets in Adult T-Cell Leukemia/Lymphoma

    Regina Wan Ju Wong, Phuong Thi Ngoc Cao, Wei Zhong Leong, Alice Wei Yee Yam, Tinghu Zhang, Shinsuke Iida, Takashi Okamoto, Ryuzo Ueda, Nathanael S. Grey, Takashi Ishida, Takaomi Sanda  

    BLOOD128 巻 ( 22 )   2016年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    Web of Science

  10. Phase I/II Multicenter Study of Romidepsin in Japanese Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma

    Michinori Ogura, Dai Maruyama, Kensei Tobinai, Toshiki Uchida, Kiyohiko Hatake, Masafumi Taniwaki, Kiyoshi Ando, Kunihiro Tsukasaki, Takashi Ishida, Naoki Kobayashi, Kenichi Ishizawa, Yoichi Tatsumi, Koji Kato, Toru Kiguchi, Takayuki Ikezoe, Eric Laille, Tokihiro Ro, Hiromi Tamakoshi, Sanae Sakurai, Tomoko Ohtsu  

    BLOOD128 巻 ( 22 )   2016年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    Web of Science

  11. Oral HDAC Inhibitor HBI8000 in Japanese Patients with Non-Hodgkin Lymphoma (NHL): Phase I Safety and Efficacy Results

    Makoto Onizuka, Kiyoshi Ando, Makoto Yoshimitsu, Takashi Ishida, S. Yoshida, Ilseung Choi, Michihiro Hidaka, Yasushi Takamatsu, Midori Nagashima, Akira Miyazato, Joachim P. Schupp, Alain Rolland, Mireille Gillings, Gloria T. Lee, Kensei Tobinai  

    BLOOD128 巻 ( 22 )   2016年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    Web of Science

  12. Monitoring of Adult T-Cell Leukemia-Lymphoma Cells in Patients Receiving Mogamulizumab, a Humanized Anti-CCR4 Monoclonal Antibody, Using T-Cell Receptor Repertoire Analysis

    Masato Saito, Takashi Ishida, Itaru Urakawa, Toshihiko Ishii, Asahi Ito, Ayako Masaki, Susumu Suzuki, Shigeru Kusumoto, Hirokazu Komatsu, Hiroshi Inagaki, Takeshi Takahashi, Ryuzo Ueda, Shinsuke Iida  

    BLOOD128 巻 ( 22 )   2016年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    Web of Science

  13. Differences between Japan and rest of world (ROW) in disease presentation and outcome of previously treated adult t-cell leukemia-lymphoma (ATL) using therapy with a monoclonal antibody to CCR4, mogamulizumab (moga).

    Adrienne Alise Phillips, Steven M. Horwitz, Graham P. Taylor, Jeffrey S. Humphrey, Kensei Tobinai, Takashi Ishida, Ryuzo Ueda  

    JOURNAL OF CLINICAL ONCOLOGY34 巻 ( 15 )   2016年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC CLINICAL ONCOLOGY  

    DOI: 10.1200/JCO.2016.34.15_suppl.e19056

    Web of Science

  14. 進行又は再発固形がん患者に対するMogamulizumabの第Ia相多施設共同医師主導治験

    黒瀬浩史, 大植祥弘, 石田高司, 飯田真介, 土井俊彦, 鈴木進, 垣見和宏, 中山睿一, 上田龍三, 岡三喜男  

    日本内科学会雑誌105 巻 ( Suppl. ) 頁: 272 - 272   2016年2月

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    記述言語:日本語   出版者・発行元:(一社)日本内科学会  

    J-GLOBAL

  15. Current Clinico-Epidemiological Characteristics of Adult T-Cell Leukemia-Lymphoma (ATL) Based on the 11th Nationwide Survey in Japan

    Kisato Nosaka, Masako Iwanaga, Kenichi Ishizawa, Yoji Ishida, Kaoru Uchimaru, Kenji Ishitsuka, Masahiro Amano, Takashi Ishida, Yoshitaka Imaizumi, Naokuni Uike, Atae Utsunomiya, Koichi Ohshima, Kazuhiro Kawai, Junji Tanaka, Yoshiki Tokura, Kensei Tobinai, Toshiki Watanabe, Kunihiro Tsukasaki  

    BLOOD126 巻 ( 23 )   2015年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    Web of Science

  16. Multicenter Phase II Study of Lenalidomide in Patients with Relapsed Adult T-Cell Leukemia-Lymphoma

    Hiroshi Fujiwara, Takashi Ishida, Kisato Nosaka, Naoya Taira, Yasunobu Abe, Yoshitaka Imaizumi, Yukiyoshi Moriuchi, Tatsuro Jo, Kenichi Ishizawa, Kensei Tobinai, Kunihiro Tsukasaki, Shigeki Ito, Makoto Yoshimitsu, Maki Otsuka, Michinori Ogura, Shuichi Midorikawa, Wanda Ruiz, Tomoko Ohtsu  

    BLOOD126 巻 ( 23 )   2015年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    Web of Science

  17. 固形がんにおけるFoxP3+ CD4 Treg除去CCR4抗体(KW-0761)療法第Ia相医師主導治験

    黒瀬 浩史, 大植 祥弘, 和田 尚, 飯田 真介, 石田 高司, 鈴木 進, 垣見 和宏, 西川 博嘉, 上田 龍三, 岡 三喜男, 中山 睿一  

    日本癌学会総会記事74回 巻   頁: J - 1173   2015年10月

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    記述言語:英語   出版者・発行元:日本癌学会  

  18. Risk Stratification of Outcomes Among Patients with Adult T-Cell Leukemia/Lymphoma Receiving Allogeneic Hematopoietic Cell Transplantation: A Retrospective Analysis of the JSHCT An Working Group

    Makoto Yoshimitsu, Ryuji Tanosaki, Koji Kato, Takashi Ishida, Ilseung Choi, Takahiro Fukuda, Yoshifusa Takatsuka, Tetsuya Eto, Naoyuki Uchida, Yukiyoshi Moriuchi, Tokiko Nagamura-Inoue, Shin-Ichiro Mori, Hisashi Sakamaki, Yoshiko Atsuta, Atae Utsunomiya  

    BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION21 巻 ( 2 ) 頁: S89 - S90   2015年2月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER SCIENCE INC  

    Web of Science

  19. Prevalence and Predictors of Medical Decision-making Incapacity Among Newly Diagnosed Older Cancer Patients: A Cross-Sectional Study

    Koji Sugano, Toru Okuyama, Shinsuke Iida, Hirokazu Komatsu, Takashi Ishida, Shigeru Kusumoto, Megumi Uchida, Tomohiro Nakaguchi, Yosuke Kubota, Yoshihiro Ito, Kazuhisa Takahashi, Tatsuo Akechi  

    PSYCHO-ONCOLOGY23 巻   頁: 286 - 287   2014年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:WILEY-BLACKWELL  

    Web of Science

  20. REACTIVATION OF HEPATITIS B VIRUS (HBV) IN HBV-RESOLVED PATIENTS WITH ADULT T-CELL LEUKEMIA/LYMPHOMA

    Haruhito Totani, Shigeru Kusumoto, Takashi Ishida, Asahi Ito, Masaki Ri, Hirokazu Komatsu, Ryuzo Ueda, Yasuhito Tanaka, Akio Niimi, Shinsuke Iida  

    ANNALS OF ONCOLOGY25 巻   2014年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:OXFORD UNIV PRESS  

    DOI: 10.1093/annonc/mdu435.73

    Web of Science

  21. hTERT is an immunogenic antigen for a novel gene-immunotherapy against adult T-cell leukemia

    Yukihiro Miyazaki, Hiroshi Fujiwara, Toshiki Ochi, Hiroaki Asai, Kozo Nagai, Jun An, Takashi Ishida, Sachiko Okamoto, Junichi Mineno, Kiyotaka Kuzushima, Hiroshi Shiku, Masaki Yasukawa  

    JOURNAL OF GENE MEDICINE16 巻 ( 7-8 ) 頁: 248 - 248   2014年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:WILEY-BLACKWELL  

    Web of Science

  22. 抗CCR4抗体モガムリズマブ (特集 HTLV-1と疾患)

    伊藤 旭, 石田 高司  

    細胞46 巻 ( 6 ) 頁: 270 - 273   2014年6月

     詳細を見る

    記述言語:日本語   出版者・発行元:ニューサイエンス社  

    CiNii Books

    その他リンク: http://search.jamas.or.jp/link/ui/2014274157

  23. 制御性T細胞解析方法の標準化に向けた多施設共同研究

    長瀬 博次, 和田 尚, 西川 博嘉, 鈴木 進, 平家 勇司, 小嶋 隆嗣, 垣見 和宏, 舩越 建, 飯田 真介, 石田 高司, 佐藤 永一, 鵜殿 平一郎, 岡 三喜男, 中山 睿一, 土岐 祐一郎, 上田 龍三  

    日本がん免疫学会総会プログラム・抄録集18回 巻   頁: 97 - 97   2014年6月

     詳細を見る

    記述言語:日本語   出版者・発行元:日本がん免疫学会  

  24. ホジキンリンパ腫におけるNY-ESO-1に対する液性および細胞性免疫応答(Humoral and cellular immune responses against NY-ESO-1 in Hodgkin's lymphoma(HL))

    鈴木 進, 石田 高司, 森 芙美子, 伊藤 旭, 楠本 茂, 小松 弘和, 吉川 和宏, 中山 睿一, 飯田 真介, 新実 彰男, 上田 龍三  

    日本癌学会総会記事72回 巻   頁: 367 - 367   2013年10月

     詳細を見る

    記述言語:英語   出版者・発行元:日本癌学会  

  25. 成人T細胞白血病・リンパ腫に対する同種移植の成績

    宇都宮 與, 石田 高司  

    血液内科66 巻 ( 6 ) 頁: 781 - 788   2013年6月

     詳細を見る

    記述言語:日本語   出版者・発行元:科学評論社  

    CiNii Books

    その他リンク: http://search.jamas.or.jp/link/ui/2013286825

  26. Randomized phase II study of mogamulizumab (KW-0761) plus VCAP-AMP-VECP (mLSG15) versus mLSG15 alone for newly diagnosed aggressive adult T-cell leukemia-lymphoma (ATL)

    Tatsuro Jo, Takashi Ishida, Shigeki Takemoto, Hitoshi Suzushima, KImiharu Uozumi, Kazuhito Yamamoto, Naokuni Uike, Yoshio Saburi, Kisato Nosaka, Atae Utsunomiya, Kensei Tobinai, Hiroshi Fujiwara, Kenji Ishitsuka, Shinichiro Yoshida, Naoya Taira, Yukiyoshi Moriuchi, Kazunori Imada, Toshihiro Miyamoto, Masao Tomonaga, Ryuzo Ueda  

    JOURNAL OF CLINICAL ONCOLOGY31 巻 ( 15 )   2013年5月

     詳細を見る

    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC CLINICAL ONCOLOGY  

    Web of Science

  27. Identification of Toyocamycin, an Agent Cytotoxic for Multiple Myeloma Cells, As a Potent Inhibitor of ER Stress-Induced XBP1 mRNA Splicing

    Masaki Ri, Etsu Tashiro, Daisuke Oikawa, Satoko Shinjo, Mio Tokuda, Yumi Yokouchi, Tomoko Narita, Ayako Masaki, Fumiko Mori, Asahi Ito, Jianming (Diane) Ding, Shigeru Kusumoto, Takashi Ishida, Hirokazu Komatsu, Yukimasa Shiotsu, Akio Niimi, Ryuzo Ueda, Takao Iwawaki, Masaya Imoto, Shinsuke Iida  

    BLOOD120 巻 ( 21 )   2012年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    Web of Science

  28. Reduced Expression of HDAC3 Contributes to the Resistance Against HDAC Inhibitor, Vorinostat (SAHA) in Mature Lymphoid Malignancies

    Jianming (Diane) Ding, Masaki Ri, Tomoko Narita, Ayako Masaki, Fumiko Mori, Asahi Ito, Shigeru Kusumoto, Takashi Ishida, Hirokazu Komatsu, Yukimasa Shiotsu, Akio Niimi, Shinsuke Iida  

    BLOOD120 巻 ( 21 )   2012年11月

     詳細を見る

    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    Web of Science

  29. Multicenter Phase II Study of Mogamulizumab (KW-0761), a Defucosylated Anti-CCR4 Antibody, in Patients with Relapsed Peripheral and Cutaneous T-Cell Lymphoma

    Takashi Ishida, Michinori Ogura, Kiyohiko Hatake, Masafumi Taniwaki, Kiyoshi Ando, Kensei Tobinai, Katsuya Fujimoto, Kazuhito Yamamoto, Toshihiro Miyamoto, Naokuni Uike, Mitsune Tanimoto, Kunihiro Tsukasaki, Kenichi Ishizawa, Junji Suzumiya, Hiroshi Inagaki, Kazuo Tamura, Shiro Akinaga, Masao Tomonaga, Ryuzo Ueda  

    BLOOD120 巻 ( 21 )   2012年11月

     詳細を見る

    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    Web of Science

  30. Human Telomerase Reverse Transcriptase-Specific T-Cell Receptor Gene Transfer Redirects T-Lymphocytes to Exert Effective Antitumor Reactivity Against Adult T-Cell Leukemia

    Yukihiro Miyazaki, Hiroshi Fujiwara, Toshiki Ochi, Hiroaki Asai, Kozo Nagai, Takashi Ishida, Sachiko Okamoto, Junichi Mineno, Kiyotaka Kuzushima, Hiroshi Shiku, Masaki Yasukawa  

    BLOOD118 巻 ( 21 ) 頁: 1784 - 1785   2011年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    Web of Science

  31. PROMISING RESULTS OF AN ANTI-CCR4 ANTIBODY, KW-0761, FOR RELAPSED ADULT T-CELL LEUKEMIA-LYMPHOMA (ATL)

    K. Tobinai, T. Ishida, K. Yamamoto, N. Uike, K. Tsukasaki, A. Utsunomiya, K. Uozumi, M. Tomonaga, R. Ueda  

    ANNALS OF ONCOLOGY22 巻   頁: 102 - 103   2011年6月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:OXFORD UNIV PRESS  

    Web of Science

  32. A Complement-Dependent Cytotoxicity-Enhancing Anti-CD20 Antibody Mediating Potent Antitumor Activity In the Humanized NOD/Shi-Scid, IL-2R gamma null Mouse Lymphoma Model

    Asahi Ito, Fumihiko Sato, Takashi Ishida, Fumiko Mori, Hisashi Takino, Atsushi Inagaki, Masaki Ri, Shigeru Kusumoto, Hirokazu Komatsu, Shinsuke Iida, Hiroshi Inagaki, Ryuzo Ueda  

    BLOOD116 巻 ( 21 ) 頁: 189 - 189   2010年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    Web of Science

  33. Multicenter Phase II Study of KW-0761, a Defucosylated Anti-CCR4 Antibody, In Relapsed Patients with Adult T-Cell Leukemia-Lymphoma (ATL)

    Takashi Ishida, Tatsuro Joh, Naokuni Uike, Kazuhito Yamamoto, Atae Utsunomiya, Shinichiro Yoshida, Yoshio Saburi, Toshihiro Miyamoto, Shigeki Takemoto, Hitoshi Suzushima, Kunihiro Tsukasaki, Kisato Nosaka, Hiroshi Fujiwara, Kenji Ishitsuka, Hiroshi Inagalci, Michinori Ogura, Shiro Akinaga, Masao Tomonaga, Kensei Tobinai, Ryuzo Ueda  

    BLOOD116 巻 ( 21 ) 頁: 129 - 130   2010年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    Web of Science

  34. CCR4抗体--悪性リンパ腫に対する新規抗体療法 (第5土曜特集 悪性リンパ腫Update) -- (新規薬剤)

    石田 高司, 上田 龍三  

    医学のあゆみ235 巻 ( 5 ) 頁: 587 - 593   2010年10月

     詳細を見る

    記述言語:日本語   出版者・発行元:医歯薬出版  

    CiNii Books

  35. Defucosylated Anti-CCR4 Monoclonal Antibody Exerts Potent ADCC against Primary ATLL Cells Mediated by Autologous Human Immune Cells in NOD/Shi-Scid, IL-2R gamma(null) Mice In Vivo

    Asahi Ito, Takashi Ishida, Atae Utsunomiya, Fumihiko Sato, Fumiko Mori, Hiroki Yano, Atsushi Inagaki, Susumu Suzuki, Hisashi Takino, Masaki Ri, Shigeru Kusumoto, Hirokazu Komatsu, Shinsuke Iida, Hiroshi Inagaki, Ryuzo Ueda  

    BLOOD114 巻 ( 22 ) 頁: 303 - 303   2009年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    Web of Science

  36. Establishment and Characterization of Bortezomib-Resistant Myeloma Cell Lines: A Possible Role of Mutated Proteasome beta 5 Subunit in Preventing the Accumulation of Unfolded Protein, Which Is Otherwise Followed by Catastrophic Endoplasmic Reticulum (ER) Stress

    Masaki Ri, Shinsuke Iida, Takayuki Nakashima, Hideyuki Miyazaki, Fumiko Mori, Asahi Ito, Atsushi Inagaki, Shigeru Kusumoto, Takashi Ishida, Hirokazu Komatsu, Yukimasa Shiotsu, Ryuzo Ueda  

    BLOOD114 巻 ( 22 ) 頁: 1451 - 1451   2009年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    Web of Science

  37. 臍帯血移植後GVHDの1例

    岡本 恵芽, 新谷 洋一, 渡辺 正一, 加藤 裕史, 森田 明理, 楠本 茂, 石田 高司  

    日本皮膚科学会雑誌119 巻 ( 10 ) 頁: 2015 - 2016   2009年9月

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    記述言語:日本語   出版者・発行元:(公社)日本皮膚科学会  

  38. Bortezomib-Induced Apoptosis in Cutaneous T-Cell Lymphoma and Adult T-Cell Leukemia/Lymphoma Cells Partially Depends on up-Regulation of Noxa, Functional Repression of Mcl-1, and Down-Regulation of C-Flip and XIAP

    Masaki Ri, Shinsuke Iida, Takashi Ishida, Asahi Ito, Hiroki Yano, Atsushi Inagaki, Jianmin Ding, Fumiko Mori, Shigeru Kusumoto, Hitokazu Komatsu, Atae Utsunomiya, Ryuzo Ueda  

    BLOOD112 巻 ( 11 ) 頁: 577 - 577   2008年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    Web of Science

  39. Expression of the ULBP Ligands for NKG2D by B-NHL Cells Plays An Important Role in Determining Their Susceptibility to Rituximab-Induced ADCC

    Atsushi Inagaki, Takashi Ishida, Hiroki Yano, Fumiko Mori, Asahi Ito, Masaki Ri, Jianmin Ding, Shigeru Kusumoto, Hirokazu Komatsu, Shinsuke Iida, Ryuzo Ueda  

    BLOOD112 巻 ( 11 ) 頁: 87 - 88   2008年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    Web of Science

  40. Clinical Significance of Serum TARC/CCL17 in ATLL Patients: High TARC/CCL17 Level Is a Significant Unfavorable Prognostic Factor.

    Atsushi Inagaki, Takashi Ishida, Hiroki Yano, Fumiko Mori, Asahi Ito, Masaki Ri, Jianmin Ding, Shigeru Kusumoto, Hirokazu Komatsu, Shinsuke Iida, Kentaro Yonekura, Shogo Takeuchi, Yosifusa Takatsuka, Atae Utsunomiya, Ryuzo Ueda  

    BLOOD112 巻 ( 11 ) 頁: 974 - 975   2008年11月

     詳細を見る

    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    Web of Science

  41. Defucosylated humanized anti-CCR4 mab KW-0761 as a novel immunotherapeutic agent for peripheral T-cell lymphoma

    T. Ishida, T. Ishii, A. Utsunomiya, A. Inagaki, H. Yano, H. Komatsu, S. Iida, K. Nakamura, M. Iwase, S. Akinaga, K. Shitara, R. Ueda  

    ANNALS OF ONCOLOGY19 巻   頁: 232 - 232   2008年6月

     詳細を見る

    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:OXFORD UNIV PRESS  

    Web of Science

  42. Mutational analysis of thrombopietin, c-MPL and Jak2 genes in essential thrombothethymia patients - Identification of concurrent mutations of c-MPL and Jak2

    Jianmin Ding, Hirokazu Komatsu, Shinsuke Iida, Asahi Ito, Hiroki Yano, Masaki Ri, Atsushi Inagaki, Shigeru Kusumoto, Takashi Ishida, Masakazu Nitta, Ryuzo Ueda  

    BLOOD110 巻 ( 11 ) 頁: 238B - 238B   2007年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    Web of Science

  43. CCR4 as a novel molecular target for immunotherapy of cancer. (vol 97, pg 1139, 2006)

    Takashi Ishida, Ryuzo Ueda  

    CANCER SCIENCE98 巻 ( 7 ) 頁: 1137 - 1137   2007年7月

     詳細を見る

    記述言語:英語   出版者・発行元:BLACKWELL PUBLISHING  

    DOI: 10.1111/j.1349-7006.2007.00522.x

    Web of Science

  44. Irinotecan (CPT-11) for multiple myeloma

    H. Yano, S. Iida, S. Kayukawa, C. Nakagawa, T. Oguri, M. Ri, A. Inagaki, T. Sanda, S. Kusumoto, T. Ishida, H. Komatsu, A. Suzuki, R. Ueda  

    HAEMATOLOGICA-THE HEMATOLOGY JOURNAL92 巻 ( 6 ) 頁: 140 - 140   2007年6月

     詳細を見る

    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:FERRATA STORTI FOUNDATION  

    Web of Science

  45. Regulatory T cell function of adult T cell leukemia/lymphoma cells

    Hiroki Yano, Takashi Ishida, Atsushi Inagaki, Toshihiko Ishii, Masaki Ri, Asahi Ito, Shigeru Kusumoto, Hirokazu Komatsu, Shinsuke Iida, Atae Utsunomiya, Ryuzo Ueda  

    AIDS RESEARCH AND HUMAN RETROVIRUSES23 巻 ( 4 ) 頁: 589 - 589   2007年4月

     詳細を見る

    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:MARY ANN LIEBERT INC  

    Web of Science

  46. Relapsed adult T cell Leukemia/Lymphoma limited in the skin after allogeneic stem cell transplantation

    Shigeru Kusumoto, Takashi Ishida, Asahi Ito, Atsushi Inagaki, Hiroki Yano, Masaki Ri, Hirokazu Komatsu, Shinsuke Iida, Hiroshi Inagaki, Ryuzo Ueda  

    AIDS RESEARCH AND HUMAN RETROVIRUSES23 巻 ( 4 ) 頁: 652 - 652   2007年4月

     詳細を見る

    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:MARY ANN LIEBERT INC  

    Web of Science

  47. The proteasome inhibitor, bortezomib, induces apoptosis and enhances suberoylanilide hydroxamic acid (SAHA)-induced cell death in HTLV-1-infected cell lines and ATLL cells

    Masaki Ri, Takashi Ishida, Atsushi Inagaki, Hiroki Yano, Toshihiko Ishii, Asahi Ito, Shigeru Kusumoto, Hirokazu Komatsu, Shinsuke Iida, Atae Utsunomiya, Ryuzo Ueda  

    AIDS RESEARCH AND HUMAN RETROVIRUSES23 巻 ( 4 ) 頁: 611 - 612   2007年4月

     詳細を見る

    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:MARY ANN LIEBERT INC  

    Web of Science

  48. Clinical significance of serum TARC/CCL17 in ATLL patients: High TARC/CCL17 level is a significant unfavorable prognostic factor

    Atsushi Inagaki, Takashi Ishida, Hiroki Yano, Toshihiko Ishii, Masaki Ri, Asahi Ito, Shigeru Kusumoto, Hirokazu Komatsu, Shinsuke Iida, Kentaro Yonekura, Shogo Takeuchi, Yoshifusa Takatsuka, Atae Utsunomiya, Ryuzo Ueda  

    AIDS RESEARCH AND HUMAN RETROVIRUSES23 巻 ( 4 ) 頁: 628 - 628   2007年4月

     詳細を見る

    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:MARY ANN LIEBERT INC  

    Web of Science

  49. CCR4 as a novel molecular target for immunotherapy in lymphoid malignancies

    石田 高司, 上田 龍三  

    日本リンパ網内系学会会誌 = The journal of the Japanese Society of Lymphoreticular Tissue46 巻   頁: 45 - 45   2006年6月

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    記述言語:日本語  

    CiNii Books

  50. DLBCLのGCB‐typeとnon GCB‐typeにおけるBcl‐2タンパク発現と染色体・遺伝子異常

    関口直宏, 小林幸夫, 楠本茂, 谷本一樹, 大西康, 横田由希子, KIM Sung‐Won, 渡辺隆, 前島亜希子, 石田高司, 稲垣宏, 松野吉宏, 上田龍三, 飛内賢正  

    臨床血液46 巻 ( 8 ) 頁: 892   2005年8月

     詳細を見る

    記述言語:日本語  

    J-GLOBAL

  51. Diffuse large B-cell lymphoma with extra BCL-2 gene signals detected by FISH analysis is associated with "non-germinal center phenotype" defined by immnohistochemistry.

    S Kusumoto, Y Kobayashi, N Sekiguchi, K Tanimoto, Y Onishi, Y Yokota, T Watanabe, A Maeshima, T Ishida, H Inagaki, Y Matsuno, R Ueda, K Tobinai  

    BLOOD104 巻 ( 11 ) 頁: 627A - 627A   2004年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    Web of Science

  52. CCR4: Chemokine receptor as a novel molecular target for immunotherapy in adult T-cell leukemia/lymphoma (ATLL).

    T Ishida, S Iida, Y Akatsuka, M Miyazaki, T Sanda, A Inagaki, S Kayukawa, M Uranishi, H Komatsu, W Atsushi, K Shitara, S Akinaga, S Nakamura, H Inagaki, A Utsunomiya, R Ueda  

    BLOOD102 巻 ( 11 ) 頁: 900A - 900A   2003年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    Web of Science

  53. Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma (ATLL): Its close association with skin involvement.and unfavorable outcome

    T Ishida, S Iida, A Utsunomiya, Y Takatsuka, H Inagaki, S Shimizu, S Kusumoto, G Takeuchi, M Ito, H Komatsu, A Wakita, T Eimoto, K Matsushima, R Ueda  

    BLOOD100 巻 ( 11 ) 頁: 275B - 275B   2002年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC HEMATOLOGY  

    Web of Science

▼全件表示

科研費 18

  1. 腫瘍浸潤能の付与による固形がんに対する新規細胞療法の開発

    研究課題/研究課題番号:21K19900  2021年7月 - 2023年3月

    科学研究費助成事業  挑戦的研究(萌芽)

    石田 高司

      詳細を見る

    担当区分:研究代表者 

    配分額:6500000円 ( 直接経費:5000000円 、 間接経費:1500000円 )

  2. CCR4を標的としたキメラ抗原受容体遺伝子改変T細胞療法の非臨床試験

    2020年4月 - 2021年3月

    日本医療研究開発機構  革新的がん医療実用化研究事業 

    研究分担者, 石田高司

  3. 成人T細胞白血病/リンパ腫に対するHTLV-1 p40Tax特異的T細胞受容体遺伝子導入アロγδ-T細胞輸注療法の研究開発

    2020年4月 - 2021年3月

    日本医療研究開発機構  再生医療実用化研究事業 

    研究分担者, 石田高司

  4. NY-ESO-1抗原特異的TCR遺伝子導入Tリンパ球輸注による同種移植後再発難治性成人T細胞白血病リンパ腫を対象とした多施設共同臨床第Ⅰ相医師主導治験 (17ck0106287h0001)

    2017年4月 - 2017年12月

    国立研究開発法人日本医療研究開発機構 (AMED)  革新的がん医療実用化研究事業 

    研究分担者, 石田高司

      詳細を見る

    資金種別:競争的資金

  5. 成人固形がんに対する標準治療確立のための基盤研究(JCOG)

    2017年4月 - 2017年12月

    独立行政法人国立がん研究センターがん研究開発費  がん研究開発費 29-A-3 

    研究分担者, 石田高司

      詳細を見る

    資金種別:競争的資金

  6. がん細胞および免疫応答解析に基づくがん免疫療法効果予測診断法の確立(16cm0106301h0001)

    2016年4月 - 2021年3月

    国立研究開発法人日本医療研究開発機構 (AMED)  次世代がん医療創生研究事業 

    研究分担者, 石田高司

      詳細を見る

    資金種別:競争的資金

  7. モガムリズマブの免疫関連有害事象;制御性T細胞除去がヒト免疫機構に及ぼす影響解明

    2016年4月 - 2019年3月

    基盤研究(B)課題番号16H04713 

    石田 高司

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    担当区分:研究代表者  資金種別:競争的資金

  8. モガムリズマブの免疫関連有害事象;制御性T細胞除去がヒト免疫機構に及ぼす影響解明

    研究課題/研究課題番号:16H04713  2016年4月 - 2019年3月

    石田 高司

      詳細を見る

    担当区分:研究代表者 

    配分額:16770000円 ( 直接経費:12900000円 、 間接経費:3870000円 )

    本研究では、モガムリズマブによる皮膚障害を発症した患者血清中に、ケラチノサイト、メラノサイトに対する自己抗体を検出した。この自己抗体によるCDC活性は、皮膚障害の重症度と相関があった。また、皮膚障害局所において、CDC活性化を示唆する、自己抗体と補体成分C1qの共局在を認めた。また、NGS解析において、皮膚障害時、血液中に新たなB細胞クローンが出現を認め、B細胞レパトアの偏りを認めた。すなわち、モガムリズマブによるTreg除去は、末梢性免疫寛容破綻により、自己反応性B細胞の残存をもたらす。この自己反応性B細胞が産生する自己抗体は、モガムリズマブの免疫関連有害事象に重要な役割を果たす。
    本研究では、モガムリズマブの制御性T細胞(Tregs)除去により、末梢性免疫寛容が破綻し、残存自己反応性B細胞が産生する自己抗体が、免疫関連有害事象の原因となることを明らかにした。現代の科学においても、B細胞の末梢性免疫寛容メカニズム、TregsがB細胞を制御するメカニズムは、明らかとなっていない。本研究成果は、ヒト免疫メカニズムの基盤的理解に貢献するものと考える。
    <BR>
    さらには、本研究成果は、PD-1、CTLA-4に対する抗体治療で認める免疫関連有害事象のさらなる理解に貢献するものである。

  9. 成人T細胞白血病・リンパ腫(ATL)に対する新規治療を開発する医師主導治験 (15ck0106132h0002)

    2015年4月 - 2017年3月

    国立研究開発法人日本医療研究開発機構 (AMED)  革新的がん医療実用化 研究事業 

    研究分担者, 石田高司

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    資金種別:競争的資金

  10. がん免疫療法における抗CCR4抗体によるTreg除去療法 ―抗体単独療法から複合免疫療法への医師主導治験― (15ck0106159h0001)

    2015年4月

    国立研究開発法人日本医療研究開発機構 (AMED)  革新的がん医療実用化 研究事業 

    研究分担者, 石田高司

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    資金種別:競争的資金

  11. モガムリズマブを用いた成人T細胞白血病リンパ腫に対する革新的治療法の確立

    研究課題/研究課題番号:25290058  2013年4月 - 2016年3月

    石田 高司

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    担当区分:研究代表者 

    配分額:17160000円 ( 直接経費:13200000円 、 間接経費:3960000円 )

    ATLに対するモガムリズマブ治療中の免疫モニタリング (MIMOGA study, UMIN000008696)に、2016年4月までに78名が登録され、免疫動態と詳細な臨床情報が蓄積されている。中間解析(49例)で、grade 2 以上の皮膚関連毒性を認めた患者群において全生存期間が延長する傾向を認め、また、腫瘍細胞が effector Treg phenotype を示す患者群において、有意な生存期間の延長を認めた。
    IDOは、ATLの免疫抑制状態に寄与し、IDO活性高値は有意な予後不良因子である。モガムリズマブを用いたATL治療に際し、IDO阻害薬との併用が有望であることを示す知見を得た。

  12. がん研究分野の特性等を踏まえた支援活動

    研究課題/研究課題番号:221S0001  2010年4月 - 2016年3月

    新学術領域研究(研究領域提案型)

    今井 浩三, 中村 祐輔

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    担当区分:研究分担者 

    がんの克服を目指す研究への支援から始まり、平成26 年度からは広く生命科学研究に携わる研究者も対象として支援を展開した。その結果、総括支援活動では若手研究者の育成ならびに今後研究支援に携わる可能性のある人材を育成し、国際学術交流を展開した。遺伝子改変マウスの供給支援、がん組織をはじめバイオリソースの提供支援等により、多くの世界的・先端的研究が展開された。日本を代表する疫学・ATL 研究では、得られた貴重な試料は11万検体を超え、多くの研究者を支援し貴重な成果を生み出した。化学療法基盤支援、ゲノム・エピゲノム支援は当初の目標を上回る成果を上げた。さらに市民講演会等により国民に支援の重要性を広報した。

  13. 低フコシル化抗体を用いた包括的がん免疫療法の開発

    研究課題/研究課題番号:22300333  2010年 - 2012年

    上田 龍三

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    担当区分:研究分担者 

    微小環境を含め、ヒト腫瘍の病態を反映する、NOGマウスヒト腫瘍モデル作成し、抗原特異的細胞傷害性T細胞(CTL)による、autologous治療実験モデルを構築した。成人T細胞白血病(ATL)細胞を移入したNOGマウスに、HTLV-1Tax特異的CTLを投与したところ、著明な治療効果が示された。免疫治療開発においては、腫瘍局所における免疫動態の解析が必須であり、本研究により構築された、治療実験モデルは今後益々重要となろう。

  14. 難治性造血器腫瘍に対する CCR4 抗体を軸とした新規包括的治療法の確立、臨床応用

    研究課題/研究課題番号:22689029  2010年 - 2012年

    石田 高司

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    担当区分:研究代表者 

    配分額:21970000円 ( 直接経費:16900000円 、 間接経費:5070000円 )

    1. HTLV-1 Tax はATLに対する有望な免疫療法の標的分子である。
    2. がん・精巣抗原 はATLに対する有望な免疫療法の標的分子である。
    3. 同種造血細胞移植療法は前処置法の種類によらずATLに長期生存をもたらし得る治療法である。
    4. モガムリズマブは ATL に対する有効な治療薬である。
    5. モガムリズマブによる Treg の除去はがん患者に対し、抗腫瘍免疫を増強する利点がある反面、自己免疫疾患を惹起しうるリスクを有する。

  15. 抗CCR4抗体の抗腫瘍効果増強を目的とした併用療法確立のための基礎的研究

    研究課題/研究課題番号:20790680  2008年 - 2009年

    石田 高司

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    担当区分:研究代表者 

    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    ヒト体内でのADCCはヒト免疫担当細胞をエフェクターとしておこるが、マウス体内においてはマウス免疫担当細胞をエフェクターとしておこる。故に、抗CCR4抗体を含む免疫療法のマウスinvivoでの抗腫瘍効果が、そのままヒトでの抗腫瘍効果を直接的に反映しないのが、これまでの限界であった。研究者はNOGマウス及び患者由来のATL腫瘍細胞を用いて、ヒトautologous免疫担当細胞移入ATL/NOGマウスモデルを確立し、低フコースADCC増強抗体であるキメラ型抗CCR4抗体の誘導するヒトADCCを、マウスinvivoで再現するモデルを確立した。本モデルにおいて、ADCCの各エフェクター細胞分画を除去し、抗腫瘍効果を評価することで、各エフェクター細胞分画のヒトADCCへの寄与の程度を解析することが可能となった。ヒトautologousADCCによる抗腫瘍効果をマウスinvivoで評価するシステムは、今回申請者らが世界で初めて報告したものである。本モデルは抗CCR4抗体をはじめADCCを主たる作用機序とする抗体薬の併用療法を含む前臨床研究に重大な貢献をすると考えられる。

  16. 腫瘍免疫に基づくホジキンリンパ腫の病態解明と新規治療法の開発研究

    研究課題/研究課題番号:19390266  2007年 - 2009年

    上田 龍三

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    担当区分:研究分担者 

    腫瘍組織に浸潤するリンパ球(TIL : Tumor infiltrating lymphocyte)中のTregの存在は、様々ながんにおいて腫瘍細胞を宿主の免疫応答から回避させるだけでなく、癌ワクチンなどの癌免疫療法が未だ十分な効果をあげられない一因と考えられており、この制御性T細胞の制御は癌免疫療法が克服すべき大きな課題と考えられている。NOGマウスを用いたホジキンリンパ腫モデルにおいてCCR4抗体の投与はホジキンリンパ腫周囲のTregの数を減少せしめた。CCR4抗体はホジキンリンパ腫のみならず、様々ながんに対し、新しい概念の薬剤としての臨床応用が期待される。

  17. 制御性T細胞に発現するCCR4を分子標的とした新規免疫療法及び臨床応用

    研究課題/研究課題番号:18790661  2006年 - 2007年

    石田 高司

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    担当区分:研究代表者 

    配分額:3500000円 ( 直接経費:3500000円 )

    前年度明らかにした,『成人T細胞性白血病リンパ腫(ATLL)において血清のIL-5が独立した有意な予後不良因子である』事実に基づき,IL-5のターゲット細胞である好酸球とATLLの病態について詳細に検討した。結果,末梢血の好酸球数高値は,ATLLにおいて有意な予後不良因子になり得ることを明らかにした。(Leuk Res.)次にCCR4を発現する代表的な腫瘍であるATLL細胞の免疫機能を詳細に解析した。申請者は健常リンパ球において,制御性T細胞は主にCD4陽性CD25強陽性CCR4陽性分画に存在することを明らかにするとともに,ATLL細胞は制御性T細胞のマスター遺伝子であるFOXP3を発現することを明らかにしてきた。今回,複数のATLL患者から得られた末梢血単核球をCD4陽性腫瘍細胞分画(ATLL細胞分画),CD4陽性非腫瘍細胞分画,抗原提示細胞分画に分離した。CD4陽性非腫瘍細胞分画を,ATLL細胞分画と共培養し,自己抗原提示細胞存在下で抗CD3抗体によりT細胞受容体刺激を加えた。結果,一部のATLL患者において,CD4陽性非腫瘍細胞分画細胞の自己の抗原提示細胞存在下でのT細胞受容体刺激に対する増殖能IFN-ロ産性能が、自己ATLL細胞分画との共培養により抑制された。すなわち一部のATLL正細胞はCD4^+CD25^+制御性T細胞としての機能を有することが明らかになったのである(Int J Cancer)。また,フコース除去キメラ型抗CCR4抗体は皮膚T細胞性リンパ腫に対し有効であることを示し,さらにこの抗腫瘍効果はインターフェロンなどのサイトカインで増強可能であることを示した(Clin Cancer Res.)。上記の基礎的研究と同時に,CCR4陽性末梢性T細胞性リンパ腫患者を対象としたフコース除去ヒト化抗CCR4抗体(KW-0761)の第I相臨床試験(ClinicalTrials.gov Identifier:NCT00355472)を着実に推し進めた。また,抗CCR4抗体による制御性T細胞の制御実験は,NOG mouseを用いた疾患モデルを作成中である。

  18. 抗体療法の科学的臨床研究

    研究課題/研究課題番号:17016065  2005年 - 2009年

    上田 龍三

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    担当区分:研究分担者 

    ケモカインレセプターCCR4が難治性T細胞性リンパ腫に特異的に発現していることを見出し、CCR4に対する低フコース型治療抗体の抗腫瘍効果をin vitro及びin vivoで示した。の開発研究を行った。さらに、これらの前臨床研究を基盤とし、CCR4陽性末梢性T 細胞性リンパ腫患者を対象としたフコース除去ヒト化抗CCR4抗体 (KW-0761)の第I相及び第II 相臨床試験を欧米諸国に先駆け日本で実施、本薬剤の承認申請のための臨床データを得た。

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