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：International Journal of Hematology  

Chimeric antigen receptor T-cell (CAR-T)-related adverse events (CAR-AEs), such as immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS), can be life-threatening and may require high-dose steroids. Identifying patients at high risk for severe CAR-AEs in a simplified way is crucial for early therapeutic intervention. This retrospective study analyzed 44 patients treated with axicabtagene ciloleucel (Axi-cel) to identify predictive factors for severe CAR-AEs. We found that grade ≥ 3 ICANS, hemophagocytic syndrome, and ICU admission were associated with a greater need for high-dose steroids, which we defined as events associated with high-dose steroids (EHS). The incidence of EHS was significantly higher in patients who developed an initial fever (≥ 38.6 °C) within 24 h of CAR-T infusion (p < 0.001). Progression-free survival (PFS) was significantly shorter in patients with EHS compared to those without EHS (p < 0.001). Additionally, patients who developed a fever within 24 h and those with a peak fever of ≥ 38.6 °C both tended to have higher peak CAR-T counts compared to other patients. Our findings suggest that an initial fever (≥ 38.6 °C) within 24 h of Axi-cel infusion may predict severe CAR-AEs requiring high-dose steroids, and that EHS is associated with worse PFS.

DOI： 10.1007/s12185-025-03957-7

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PubMed

J-GLOBAL

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  

Historically, the presence of measurable disease has been considered essential to stimulate CAR T-cell expansion and persistence. However, the kinetics of CAR T cells in patients achieving complete response (CR) before infusion remain poorly understood. This study aimed to evaluate the outcomes and CAR T-cell kinetics in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients stratified by pre-infusion disease status. In this retrospective analysis of 87 patients treated at a single institution, 23 (26.4%) were in CR and 64 (73.6%) were in non-CR prior to CAR T-cell infusion. Patients in CR exhibited significantly better progression-free survival (PFS) and overall survival compared to non-CR patients. Peripheral blood CAR T-cell kinetics, including the proportion and absolute counts of CAR T cells, CD4+ CAR T cells and CD8+ CART cells, showed no significant differences between CR and non-CR groups. These findings were consistent across different CAR T-cell products, whether 4-1BB- or CD28-based. Moreover, an analysis of patients achieving complete metabolic response (CMR) by PET-CT confirmed comparable CAR T-cell expansion and persistence in both CMR and non-CMR patients. Our findings demonstrate that CAR T-cell therapy achieves robust expansion and favourable survival outcomes in CR patients, even in the absence of measurable disease.

DOI： 10.1111/bjh.20186

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PubMed

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 for Immunotherapy of Cancer  

Background Whereas chimeric antigen receptor gene modified T (CAR-T) cell therapy has been clinically applied to malignant lymphomas and multiple myeloma, CAR-T cell therapy for solid tumors has so far not reached clinical application. Epithelial V-like antigen 1 (Eva1), transcribed from myelin protein zero-like 2 (MPZL2), is a small surface protein highly expressed on various tumor cells. We selected Eva1 as a novel solid tumor-target antigen because of its broad expression across various tumor types. The purpose of the present study is to develop and optimize CAR-T cells targeting Eva1. Method We prepared various humanized single chain variable fragment sequences based on a mouse anti-human Eva1 monoclonal antibody. We constructed six humanized Eva1CAR-Ts and selected one that maintained specificity and good cellular proliferation after antigen stimulation. We further optimized the length of the extracellular spacer domain and the choice of the intracellular domain in vitro and in two different xenograft mouse models. Results We confirmed Eva1 expression on various tumor cell lines by flow cytometry and analysis of public database, but we also observed that normal monocytes weakly expressed Eva1. A combination of short spacer domain and 4-1BB or CD79A/CD40 intracellular domain provided higher treatment efficacy both in vitro and in vivo. The cytokine release on autologous monocyte stimulation to Eva1CAR-T cells was comparable to that on autologous B cell stimulation to CD19CAR-T cells. Humanized Eva1CAR-T cells demonstrated excellent therapeutic efficacy by infusing a single dose of Eva1CAR-T cells (1×10⁶) in both NCI-H1975 lung cancer and CFPAC-1 pancreatic cancer cell line grafted model. Conclusions In summary, these data suggest that humanized Eva1CAR-T has promising therapeutic potential for the treatment of various Eva1-positive solid tumors. Regarding on-target/off-tumor recognition, further detailed analyses of the Eva1CAR-T cell responses to normal tissues are needed.

DOI： 10.1136/jitc-2024-009825

Open Access

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PubMed

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 Communications  

Chimeric antigen receptor (CAR) T cell is a promising therapy for cancer, but factors that enhance the efficacy of CAR T cell remain elusive. Here we perform a genome-wide CRISPR screening to probe genes that regulate the proliferation and survival of CAR T cells following repetitive antigen stimulations. We find that genetic ablation of CUL5, encoding a core element of the multi-protein E3 ubiquitin-protein ligase complex, cullin-RING ligase 5, enhances human CD19 CAR T cell expansion potential and effector functions, potentially via the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. In this regard, CUL5 knockout CD19 CAR T cells show sustained STAT3 and STAT5 phosphorylation, as well as delayed phosphorylation and degradation of JAK1 and JAK3. In vivo, shRNA-mediated knockdown of CUL5 enhances CD19 CAR T treatment outcomes in tumor-bearing mice. Our findings thus imply that targeting CUL5 in the ubiquitin system may enhance CAR T cell effector functions to enhance immunotherapy efficacy.

DOI： 10.1038/s41467-024-54794-x

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PubMed

出版者・発行元：医歯薬出版  

DOI： 10.32118/ayu289090685

CiNii Research

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

Chimeric antigen receptor T (CAR-T) cells targeting multiple antigens (Ag), may reduce the risk of immune escape following the loss of the target Ag and further increase the efficacy of treatment. We developed dual-targeting CAR-T cells that target CD19 and CD37 Ags and evaluated their antitumor effects. CD19/CD37 dual CAR-T cells were generated using cotransduction and simultaneous gene transfer of two types of lentiviral vectors transferring CD19CAR or CD37CAR genes, including the intracellular domains of CD28 and CD3z signaling domains. These dual CAR-T cells contained three fractions: CD19/CD37 bispecific CAR-T cells, single CD19CAR-T cells, and single CD37CAR-T cells. In the functional evaluation of CAR-T cells in vitro, CD19/CD37 dual CAR-T cells showed adequate proliferation and cytokine production in response to CD19 and CD37 antigen stimulation alone or in combination. Evaluation of intracellular signaling revealed that dual CAR-T cell-mediated signals were comparable with single CAR-T cells in response to CD19- and CD37-positive B-cell tumors. Although the cytotoxicity of CD19/CD37 dual CAR-T cells in both CD19- and CD37-positive B-cell tumors was similar to that of single CD19 and CD37CAR-T cells, against CD19 and CD37 Ag-heterogeneous tumor, dual CAR-T cells demonstrated significantly superior tumor lysis compared with single CAR-T cells. Furthermore, CD19/CD37 dual CAR-T cells effectively suppressed Ag-heterogeneous Raji cells in a xenograft mouse model. Collectively, these results suggest that CD19/CD37 dual CAR-T cells may be effective target-Ag-loss B-cell tumor models in vitro and in vivo, which represents a promising treatment for patients with relapsed/refractory B-cell malignancies.

DOI： 10.1158/1535-7163.MCT-23-0408

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PubMed

Web of Science

DOI： 10.1182/blood-2023-179842

Web of Science

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  

To determine the efficacy of SARS-CoV-2 mRNA vaccination for allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients, we measured antibody titer serially in 92 allo-HSCT patients. Among the evaluable 87 patients, median age at vaccination was 53 years (range, 18–75). The average time between allo-HSCT and vaccination was 3.3 years (range, 0.5–15.7). One month after the second dose, 70 patients (80.5%) had a positive response, whereas 17 patients (19.5%) had a negative response (< 20 U/mL). Only patients older than 44 years had a negative response. Low IgM level was the only significant predictor of vaccine failure in elderly patients. When antibody response before and after the third vaccination was examined in 47 patients, antibodies increased significantly from a median of 18.3 U/mL to 312.6 U/mL (P < 0.01). The median antibody titer after the third vaccination of healthy individuals (n = 203) was 426.4 U/mL, which was comparable to that of patients (P = 0.2). The antibody titer after the third mRNA vaccination increased even in patients whose first two mRNA vaccinations failed. These findings suggest that allo-HSCT recipients should receive the mRNA vaccine regularly.

DOI： 10.1007/s12185-023-03648-1

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PubMed

記述言語：英語   出版者・発行元：(一社)日本血液学会  

記述言語：日本語   出版者・発行元：(一社)日本組織適合性学会  

記述言語：英語  

For successful chimeric antigen receptor T (CAR-T) cell therapy, CAR-T cells must be manufactured without failure caused by suboptimal expansion. In order to determine risk factors for CAR-T cell manufacturing failure, we performed a nationwide cohort study in Japan and analysed patients with diffuse large B-cell lymphoma (DLBCL) who underwent tisagenlecleucel production. We compared clinical factors between 30 cases that failed (7.4%) with those that succeeded (n = 378). Among the failures, the proportion of patients previously treated with bendamustine (43.3% vs. 14.8%; p < 0.001) was significantly higher, and their platelet counts (12.0 vs. 17.0 × 10⁴/μL; p = 0.01) and CD4/CD8 T-cell ratio (0.30 vs. 0.56; p < 0.01) in peripheral blood at apheresis were significantly lower than in the successful group. Multivariate analysis revealed that repeated bendamustine use with short washout periods prior to apheresis (odds ratio [OR], 5.52; p = 0.013 for ≥6 cycles with washout period of 3–24 months; OR, 57.09; p = 0.005 for ≥3 cycles with washout period of <3 months), low platelet counts (OR, 0.495 per 105/μL; p = 0.022) or low CD4/CD8 ratios (<one third) (OR, 3.249; p = 0.011) in peripheral blood at apheresis increased the risk of manufacturing failure. Manufacturing failure remains an obstacle to CAR-T cell therapy for DLBCL patients. Avoiding risk factors, such as repeated bendamustine administration without sufficient washout, and risk-adapted strategies may help to optimize CAR-T cell therapy for DLBCL patients.

DOI： 10.1111/bjh.18831

Open Access

CiNii Research

記述言語：英語   出版者・発行元：British Journal of Haematology  

For successful chimeric antigen receptor T (CAR-T) cell therapy, CAR-T cells must be manufactured without failure caused by suboptimal expansion. In order to determine risk factors for CAR-T cell manufacturing failure, we performed a nationwide cohort study in Japan and analysed patients with diffuse large B-cell lymphoma (DLBCL) who underwent tisagenlecleucel production. We compared clinical factors between 30 cases that failed (7.4%) with those that succeeded (n = 378). Among the failures, the proportion of patients previously treated with bendamustine (43.3% vs. 14.8%; p < 0.001) was significantly higher, and their platelet counts (12.0 vs. 17.0 × 104/μL; p = 0.01) and CD4/CD8 T-cell ratio (0.30 vs. 0.56; p < 0.01) in peripheral blood at apheresis were significantly lower than in the successful group. Multivariate analysis revealed that repeated bendamustine use with short washout periods prior to apheresis (odds ratio [OR], 5.52; p = 0.013 for ≥6 cycles with washout period of 3–24 months; OR, 57.09; p = 0.005 for ≥3 cycles with washout period of <3 months), low platelet counts (OR, 0.495 per 105/μL; p = 0.022) or low CD4/CD8 ratios (<one third) (OR, 3.249; p = 0.011) in peripheral blood at apheresis increased the risk of manufacturing failure. Manufacturing failure remains an obstacle to CAR-T cell therapy for DLBCL patients. Avoiding risk factors, such as repeated bendamustine administration without sufficient washout, and risk-adapted strategies may help to optimize CAR-T cell therapy for DLBCL patients.

DOI： 10.1111/bjh.18831

Open Access

Scopus

PubMed

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  

キメラ抗原受容体遺伝子導入T細胞(CAR-T)療法後1ヵ月以内の短期的なCAR-Tの体内動態と治療成績の関係は解明されていない。今回,tisagenlecleucel療法を行った再発難治性びまん性大細胞型B細胞リンパ腫患者13例において,CAR-T輸注後1ヵ月までのCAR-Tの体内動態をフローサイトメトリー法と定量PCR法を用いて定量的に測定し,治療成績との関係について解析した。CAR-T全体の解析では,短期的なCAR-Tの体内動態と治療成績について明らかな関連を認めなかった。しかし,CD4/CD8サブセットに着目すると,CD4+ CAR-Tが治療反応良好例で増加することが認められた。一方,CD8+ CAR-Tは治療反応不良例で増加していた。また,サイトカイン放出症候群を生じた症例では,CAR-Tの増殖が顕著であった。したがって,CAR-Tの治療反応性を予測するためには,輸注後早期のCD4+ CAR-Tの増殖が重要であることが示唆された。(著者抄録)

DOI： 10.11406/rinketsu.64.167

その他リンク： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01540&link_issn=&doc_id=20230410170001&doc_link_id=1390014183338635904&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390014183338635904&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_2.gif

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

Myelodysplastic syndrome is associated with the development of autoinflammatory conditions, such as recurrent fever, polymyalgia, arthralgia, and erythema. Trisomy 8 is a common chromosomal abnormality in patients with myelodysplastic syndrome. Myelodysplastic syndrome with trisomy 8 involves autoinflammatory conditions, especially Behçet’s disease-like symptoms with intestinal mucosal damage. MEFV variants, particularly those in exon 10, are pathogenic in familial Mediterranean fever, the most common autoinflammatory disease, presenting typical symptoms such as periodic fever and pleuritis/pericarditis/ peritonitis. MEFV variants outside exon 10 are common in Japanese patients with familial Mediterranean fever and are associated with atypical symptoms, including myalgia and erythema. MEFV variants in myelodysplastic syndrome with trisomy 8 have rarely been investigated, although myelodysplastic syndrome with trisomy 8 might develop autoinflammatory conditions similar to those in familial Mediterranean fever. We encountered a 67-year-old man who had myelodysplastic syndrome with trisomy 8 and multiple MEFV variants outside exon 10. He presented with periodic fever, as well as chest/abdominal pain, myalgia, and erythema, although the symptoms did not fulfill the diagnostic criteria of familial Mediterranean fever. We discussed the possibility that these symptoms are modified by MEFV variants outside exon 10 in myelodysplastic syndrome with trisomy 8

DOI： 10.18999/nagjms.85.1.195

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記述言語：日本語   出版者・発行元：一般社団法人 日本血液学会  

<p>実臨床におけるB細胞性急性リンパ芽球性白血病に対するキメラ抗原受容体T（CAR-T）細胞製造成否の状況を明らかにするため，tisagenlecleucel（tisa-cel）製造を実施された81症例を解析した。アフェレーシス時年齢中央値は13歳（1～25），男性47例（58.0％），前治療数の中央値4（1～9），同種移植歴とinotuzumab ozogamicin，blinatumomabの使用歴は，それぞれ51例（63.0％），26例（32.1％），37例（45.7％）に認めた。アフェレーシス時末梢血芽球比率，CD3陽性細胞数は中央値0％（0～91.5），611/µ<i>l</i>（35～4,210）で，出荷されたCD3陽性細胞数は中央値2.2×10⁹個（0.5～8.3）であった。濃厚な前治療歴のある症例が含まれたが，製造失敗は見られなかった。引き続き製造失敗の状況を注視する必要がある。</p>

DOI： 10.11406/rinketsu.64.331

PubMed

CiNii Research

J-GLOBAL

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>キメラ抗原受容体遺伝子導入T細胞（CAR-T）療法後1ヶ月以内の短期的なCAR-Tの体内動態と治療成績の関係は解明されていない。今回，tisagenlecleucel療法を行った再発難治性びまん性大細胞型B細胞リンパ腫患者13例において，CAR-T輸注後1ヶ月までのCAR-Tの体内動態をフローサイトメトリー法と定量PCR法を用いて定量的に測定し，治療成績との関係について解析した。CAR-T全体の解析では，短期的なCAR-Tの体内動態と治療成績について明らかな関連を認めなかった。しかし，CD4/CD8サブセットに着目すると，CD4⁺ CAR-Tが治療反応良好例で増加することが認められた。一方，CD8⁺ CAR-Tは治療反応不良例で増加していた。また，サイトカイン放出症候群を生じた症例では，CAR-Tの増殖が顕著であった。したがって，CAR-Tの治療反応性を予測するためには，輸注後早期のCD4⁺ CAR-Tの増殖が重要であることが示唆された。</p>

DOI： 10.11406/rinketsu.64.167

PubMed

CiNii Research

J-GLOBAL

記述言語：日本語   出版者・発行元：(一社)日本組織適合性学会  

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  

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  

J-GLOBAL

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  

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  

Genomic deletion of donor–patient-mismatched HLA alleles in leukemic cells is a major cause of relapse after allogeneic hematopoietic stem cell transplantation (HSCT). Mismatched HLA is frequently lost as an individual allele or a whole region in HLA-class I, however, it is downregulated in HLA-class II. We hypothesized that there might be a difference in T cell recognition capacity against epitopes associated with HLA-class I and HLA-class II and consequently such allogeneic immune pressure induced HLA alterations in leukemic cells. To investigate this, we conducted in vitro experiments with T cell receptor-transduced T (TCR-T) cells. The cytotoxic activity of NY-ESO-1-specific TCR-T cells exhibited similarly against K562 cells with low HLA-A*02:01 expression. However, we demonstrated that the cytokine production against low HLA-DPB1*05:01 expression line decreased gradually from the HLA expression level approximately 2-log lower than normal expressors. Using sort-purified leukemia cells before and after HSCT, we applied the next-generation sequencing, and revealed that there were several marked downregulations of HLA-class II alleles which demonstrated consistently low expression from pre-transplantation. The marked downregulation of HLA-class II may lead to decreased antigen recognition ability of antigen-specific T cells and may be one of immune evasion mechanism associated with HLA-class II downregulation.

DOI： 10.1007/s12185-021-03273-w

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PubMed

記述言語：日本語  

DOI： 10.1182/blood-2021-150469

Web of Science

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

Adoptively transferred CD19 chimeric antigen receptor (CAR) T cells have led to impressive clinical outcomes in B cell malignancies. Beyond induction of remission, the persistence of CAR-T cells is required to prevent relapse and provide long-term disease control. To improve CAR-T cell function and persistence, we developed a composite co-stimulatory domain of a B cell signaling moiety, CD79A/CD40, to induce a nuclear translocating signal, NF-κB, to synergize with other T cell signals and improve CAR-T cell function. CD79A/CD40 incorporating CD19CAR-T cells (CD19.79a.40z) exhibited higher NF-κB and p38 activity upon CD19 antigen exposure compared with the CD28 or 4-1BB incorporating CD19CAR-T cells (CD19.28z and CD19.BBz). Notably, we found that CD19.79a.40z CAR-T cells continued to suppress CD19⁺ target cells throughout the co-culture assay, whereas a tendency for tumor growth was observed with CD19.28z CAR-T cells. Moreover, CD19.79a.40z CAR-T cells exhibited robust T cell proliferation after culturing with CD19⁺ target cells, regardless of exogenous interleukin-2. In terms of in vivo efficiency, CD19.79a.40z demonstrated superior anti-tumor activity and in vivo CAR-T cell proliferation compared with CD19.28z and CD19.BBz CD19CAR-T cells in Raji-inoculated mice. Our data demonstrate that the CD79A/CD40 co-stimulatory domain endows CAR-T cells with enhanced proliferative capacity and improved anti-tumor efficacy in a murine model.

DOI： 10.1016/j.ymthe.2021.04.038

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PubMed

記述言語：英語   出版者・発行元：(一社)日本血液学会  

記述言語：英語   出版者・発行元：(一社)日本血液学会  

記述言語：英語   出版者・発行元：(一社)日本血液学会  

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）  

DOI： 10.1093/infdis/jiz491

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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  

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  

記述言語：日本語   出版者・発行元：(公社)日本皮膚科学会  

J-GLOBAL

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  

J-GLOBAL

J-GLOBAL

J-GLOBAL

記述言語：英語  

J-GLOBAL

記述言語：英語  

J-GLOBAL

記述言語：英語  

J-GLOBAL

記述言語：日本語   出版者・発行元：(一社)日本組織適合性学会  

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  

J-GLOBAL

開催年月日： 2025年9月

記述言語：日本語   会議種別：口頭発表（一般）  

開催年月日： 2025年7月

記述言語：英語   会議種別：口頭発表（一般）  

開催年月日： 2025年5月

記述言語：英語   会議種別：ポスター発表  

開催年月日： 2025年5月

記述言語：日本語   会議種別：口頭発表（一般）  

開催年月日： 2025年5月

記述言語：日本語   会議種別：口頭発表（一般）  

開催年月日： 2022年6月

開催年月日： 2021年7月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催年月日： 2021年4月

記述言語：日本語   会議種別：口頭発表（一般）  

開催年月日： 2019年3月

記述言語：英語  

開催年月日： 2017年12月

記述言語：英語  

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開催年月日： 2017年12月

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開催年月日： 2009年

開催年月日： 2009年

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開催年月日： 2008年9月

記述言語：日本語  

開催年月日： 2008年9月

記述言語：日本語