研究者詳細 - 赤塚　美樹

講演・口頭発表等 - 赤塚　美樹

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交差適合試験の省略と簡略化を考える安全性を重視した高感度交差適合試験の運用

松浦秀哲, 杉浦縁, 荒川章子, 赤塚美樹

日本輸血細胞治療学会誌 2018年4月 (一社)日本輸血・細胞治療学会

再発急性骨髄性白血病において微小転座から複数のスプライシング産物を認めたRUNX1-GRIK2融合遺伝子(Multiple splicing transcripts from RUNX1-GRIK2 fusion in a cryptic translocation in a relapsed AML)

Abe Akihiro, Yamamoto Yukiya, Okamoto Akinao, Tokuda Masutaka, Inaguma Yoko, Yanada Masamitsu, Kanie Tadaharu, Tomita Akihiro, Akatsuka Yoshiki, Okamoto Masataka, Kameyama Toshiki, Maeda Akira, Emi Nobuhiko

臨床血液 2017年9月 (一社)日本血液学会-東京事務局

Rasburicase投与後の抗体産生の頻度と抗体価の推移に関する研究

安藤舞子, 赤塚美樹, 伊藤佳織, 徳田倍将, 稲熊容子, 岡本晃直, 蟹江匡治, 柳田正光, 山本幸也, 冨田章裕, 岡本昌隆, 山田成樹, 恵美宣彦

臨床血液 2017年9月 (一社)日本血液学会-東京事務局

初発皮下脂肪織炎様T細胞リンパ腫(SPTCL)に対するPSL単剤治療の有効性

加古寿志, 岡本晃直, 冨田章裕, 稲熊容子, 徳田倍将, 蟹江匡治, 柳田正光, 山本幸也, 赤塚美樹, 岡本昌隆, 恵美宣彦

臨床血液 2017年6月 (一社)日本血液学会-東京事務局

健常者におけるカラム凝集法と試験管法の抗体価測定の差異の検討

杉浦縁, 赤塚美樹, 松浦秀哲, 松野貴洋, 荒川章子, 及川彰太, 永田梨奈, 磯貝聡衣, 村松知佳, 柴田亜委, 岡本晃直, 恵美宣彦

日本輸血細胞治療学会誌 2017年6月 (一社)日本輸血・細胞治療学会

当院におけるカリウム吸着フィルターの使用状況

磯貝聡衣, 松浦秀哲, 杉浦縁, 坂本悠斗, 永田梨奈, 及川彰太, 松野貴洋, 西垣亮, 加藤友理, 村松知佳, 柴田亜委, 荒川章子, 岡本晃直, 恵美宣彦, 赤塚美樹

日本輸血細胞治療学会誌 2017年4月 (一社)日本輸血・細胞治療学会

Phase 1 Clinical Trial of Adoptive Immunotherapy for Acute Myelogenous Leukemia and Myelodysplastic Syndrome, Using Gene-Modified Autologous Lymphocytes Expressing WT1-Specific T-Cell Receptor 国際会議

Kazushi Tanimoto, Hiroshi Fujiwara, Isao Tawara, Masahiro Masuya, Shinichi Kageyama, Tetsuya Nishida, Makoto Murata, Seitaro Terakura, Yoshiki Akatsuka, Hiroaki Ikeda, Yoshihiro Miyahara, Ikuei Nukaya, Kazutoh Takesako, Nobuhiko Emi, Naoyuki Katayama, Hiroshi Shiku, Masaki Yasukawa

Blood 2016年12月2日 American Society of Hematology

開催年月日： 2016年12月

記述言語：英語会議種別：口頭発表（招待・特別）

<title>Abstract</title>
Elderly patients (pts) with acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome (MDS) particularly who are ineligible for allogeneic hematopoietic stem cell transplantation (allo-HSCT) and have disease relapse after allo-HSCT still have a poor prognosis. Thus, the development of novel treatment option providing higher response rate and prolonged survival time for those patients still remains an unmet need. Because not a few clinical and preclinical studies have described a promising value of Wilms Tumor 1 (WT1), a leukemia-associated antigen as a therapeutic target of antileukemia immunotherapy, we conducted a clinical study of novel adoptive immunotherapy using gene-modified autologous lymphocytes expressing WT1-specific T-cell receptor (TCR) for the treatment of refractory AML and high-risk MDS.

A multicenter phase 1 study was conducted to assess feasibility, safety and preliminary antileukemia reactivity of patient-derived gene-modified lymphocytes expressing WT1-specific TCR. Antigen-specific TCR-gene transfer may cause a serious autoimmune disease mediated by mispaired TCR between introduced and endogenous TCR α/β chains. To avoid that, we established a retroviral vector system encoding siRNAs for endogenous TCR genes (siTCR vector). We conducted a first-in-human clinical trial employing this siTCR vector. After given written informed consents, mononuclear cells were collected from at most 200ml of peripheral blood (PB) from each patient. Then, proliferating lymphocytes pre-cultured with IL-2, anti-CD3 antibody and RetroNectinTM were infected with a retroviral vector, MS3-WT1-siTCR composed of DNAs encoding WT1235-243/HLA-A*24:02 complex specific TCR-α/β chains and siRNAs against endogenous TCR genes. Expanded gene-modified lymphocytes (WT1-siTCR/T cells) in additional culture for 13-14 more days were harvested and frozen until use. Eligibility included HLA-A*24:02 positive pts with refractory AML or high-risk MDS, > 20 y.o, ineligible for allo-HSCT and performance status of 0 to 2. WT1-siTCR/T cells were intravenously infused twice on days 0 and 28. Heteroclitic WT1235-243 ninemer peptide (300mg) emulsified with MontanideTM was given subcutaneously on day 2 and 16 after the second infusion. Besides safety assays, kinetics of WT1-siTCR/T cells in PB, immunological responses and residual leukemia burden determined by qRT-PCR for WT1 mRNA were serially measured until day 58 since the first infusion.

Among 12 pts enrolled, 8 pts (5 AML, 3 MDS) with a median age of 68.5 y. received study treatment. Three pts received 2x108 cells/ infusion (cohort 1), 3 received 1x109 cells/ infusion (cohort 2), and 2 received extra-cohort doses. Median follow-up time after the first infusion was 257 days (as June 13, 2016). At the first infusion, all pts contracted progressive disease. Circulatory WT1-siTCR/T cells retaining the target reactivity appeared immediately after each infusion, peaked between 1 to 3 days, and declined thereafter. WT1 peptide vaccination did not seem to affect the transition of infused cells. Values of WT1 mRNA in PB were transiently suppressed in all pts and declined in 4 pts thereafter. Clinical outcomes included one with stable disease and 2 pts with partial remission (PR). In one with PR, the epitope-spreading phenomenon was suggested. In all pts, no serious adverse events associated with infused WT1-siTCR/T cells were observed.

Adoptive transfer of autologous WT1-siTCR/T cells was feasible and safe. Although the persistence of infused WT1-siTCR/T cells was limited, infused WT1-siTCR/T cells at least seemed to be involved in the antileukemia reactivity.

<sec>
<title>Disclosures</title>
Tawara: Astellas: Honoraria. Akatsuka:Takara Bio Inc.: Consultancy. Nukaya:Takara Bio Inc.: Employment. Takesako:Takara Bio Inc.: Employment.

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赤塚美樹.遺伝子改変T細胞療法の開発の歴史と将来. 招待有り国際会議

赤塚　美樹

第78回日本血液学会総会.教育講演 49

遺伝子改変T細胞療法の開発の歴史と将来. 国際会議

赤塚　美樹

第78回日本血液学会総会

t(4;12)を伴うAML症例におけるETV6転座によるPDGFRAおよびGSX2の転写活性化(Transcriptional activation of PDGFRA and GSX2 by ETV6 translocation in a case of AML with t(4;12))

Abe Akihiro, Mizuta Shuichi, Yamamoto Yukiya, Okamoto Akinao, Iba Sachiko, Tokuda Masutaka, Inaguma Yoko, Yanada Masamitsu, Morishima Satoko, Kanie Tadaharu, Tomita Akihiro, Akatsuka Yoshiki, Okamoto Masataka, Kameyama Toshiki, Maeda Akira, Emi Nobuhiko

臨床血液 2016年9月 (一社)日本血液学会-東京事務局

DLBCL患者における単核球及び血清中と腫瘍中EBVウイルス量の関係

岡本晃直, 柳田正光, 岡本昌隆, 稲熊容子, 徳田倍将, 森島聡子, 蟹江匡治, 山本幸也, 水田秀一, 冨田章裕, 赤塚美樹, 吉川哲史, 中村栄男, 溝口良順, 恵美宣彦

日本リンパ網内系学会会誌 2016年8月 (一社)日本リンパ網内系学会

Basics and development of CAR-T cell therapy and its clinical applications. 招待有り国際会議

赤塚　美樹

第14回日本臨床腫瘍学会総会. 教育講演２

血液浄化・ステロイドパルスが奏効したEBV関連血球貪性リンパ組織球症の1例

野村宣徳, 岡本晃直, 稲熊容子, 徳田倍将, 森島聡子, 蟹江匡治, 柳田正光, 山本幸也, 水田秀一, 冨田章裕, 赤塚美樹, 岡本昌隆, 恵美宣彦

臨床血液 2016年6月 (一社)日本血液学会-東京事務局

当院における異型適合赤血球輸血の状況

荒川章子, 杉浦縁, 松浦秀哲, 松野貴洋, 及川彰太, 永田梨奈, 磯貝聡衣, 加藤友理, 村松知佳, 柴田亜委, 倉橋美千代, 岡本晃直, 水田秀一, 赤塚美樹, 恵美宣彦

日本輸血細胞治療学会誌 2016年6月 (一社)日本輸血・細胞治療学会

輸血依存MDS及びAAにおける、デフェラシロクス時代の鉄過剰症及び生存/死因の検討

岡本晃直, 加藤友理, 村松知佳, 松浦秀哲, 荒川章子, 杉浦縁, 徳田倍将, 森島聡子, 水田秀一, 赤塚美樹, 恵美宣彦

日本輸血細胞治療学会誌 2016年4月 (一社)日本輸血・細胞治療学会

当院における新生児・小児に対する赤血球輸血の後方視的検討

加藤友理, 松浦秀哲, 永田梨奈, 磯貝聡衣, 村松知佳, 荒川章子, 倉橋美千代, 杉浦縁, 岡本晃直, 水田秀一, 赤塚美樹, 恵美宣彦

日本輸血細胞治療学会誌 2016年4月 (一社)日本輸血・細胞治療学会

悪性リンパ腫における末梢血EBV-DNA量測定の意義

岡本晃直, 柳田正光, 三浦浩樹, 稲熊容子, 德田倍将, 蟹江匡治, 山本幸也, 冨田章裕, 赤塚美樹, 岡本昌隆, 吉川哲史, 恵美宣彦

藤田学園医学会誌 2016年藤田学園医学会

Adoptive Transfer of WT1-Specific TCR Gene-Transduced Lymphocytes in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia 国際会議

Isao Tawara, Masahiro Masuya, Shinichi Kageyama, Tetsuya Nishida, Seitaro Terakura, Makoto Murata, Hiroshi Fujiwara, Yoshiki Akatsuka, Hiroaki Ikeda, Yoshihiro Miyahara, Daisuke Tomura, Ikuei Nukaya, Kazutoh Takesako, Nobuhiko Emi, Masaki Yasukawa, Naoyuki Katayama, Hiroshi Shiku

Blood 2015年12月3日 American Society of Hematology

開催年月日： 2015年12月

記述言語：英語会議種別：口頭発表（一般）

<title>Abstract</title>
Wilms' Tumor 1 (WT1) is expressed in a majority of MDS and AML cells and mRNA of WT1 in peripheral blood and bone marrow is monitored as a marker of minimal residual disease of AML and MDS. Several WT1 protein-derived epitopes that are recognized by cytotoxic T lymphocytes (CTLs) along with HLA molecules are determined. In vitro study and WT1 peptide vaccine trials have demonstrated that WT1-specfic CD8+ T cells with cytotoxic activity can be induced. Adoptive T cell therapy using ex vivo expanded WT1-specific CTLs or WT1-specific T-cell receptor (TCR)-gene transduced cells are potentially effective to refractory MDS and AML.

Antigen-specific TCR-gene transfer may cause serious autoimmune disease by mispairing of introduced and endogenous TCR chains that recognize auto-antigens. We established a retroviral vector system encoding siRNAs for endogenous TCR genes to eliminate TCR-mispairing. Using the siRNA-encoding viral vector, we have conducted a first-in-man trial of WT1-specfic TCR-gene transduced T cell transfer. In the trial, we evaluate the safety of the TCR T cell transfer in patients with MDS and AML, and assess in vivo kinetics of the transferred cells. The study was designed as cell-dose escalation with three cohorts of 2x108, 1x109, and 5x109cells per infusion.

Peripheral blood mononuclear cells were collected from each patient. Then, the cells were cultured with IL-2, anti-CD3 antibody, and RetroNectin®. Proliferating lymphocytes were infected with a retroviral vector, MS3-WT1-siTCR, which was constructed from DNA encoding WT1235-243/HLA*A24:02 specific TCR-α and -β chains and siRNAs for endogenous TCR genes. After 13-14 days in culture, the lymphocytes were harvested and frozen until infusion.

Patients were enrolled to the clinical trial if they were refractory AML or MDS ineligible for allogeneic stem cell transplant, positive for HLA-A*24:02, had performance status of 0 to 2, and had normal organ function. WT1-TCR T cells were infused intravenously twice on days 0 and 28. Modified WT1235-243peptide (300μg) emulsified with Montanide, was given subcutaneously on day 2 and 16 after the second infusion.

To date, 5 patients (4 MDS and 1 AML cases) with a median age of 69 years, received WT1-TCR T cells. Three received 2x108 cells (cohort 1) and 2 received 1x109 cells (cohort 2) per infusion, respectively. We did not see any severe adverse events related to the cell infusion or peptide vaccination. No renal or mesothelial damages were observed. We then assessed transduced TCR-gene copy numbers in peripheral blood samples collected at multiple pre-determined time points until day 58.TCR-gene marked cells were detected in all patients after the cell infusion. They appeared immediately after the infusion, reaching peak levels between 1 and 3 days. Then, the levels gradually declined. After the second infusion, which was followed by peptide vaccination, the cells appeared in the similar way to the first cycle. The peptide vaccine did not seem to affect the peripheral cell kinetics. Dose-dependent kinetics were shown between the cohort 1(2 x108 cells) and the cohort 2 (1x109cells). In two patients, transient decline of peripheral abnormal cells that were MDS-related erythroblasts, and decrease of bone marrow blasts were observed, respectively.

Although the clinical trial is still ongoing, transfer of WT1-TCR-gene transduced lymphocyte to MDS and AML patients is safe and tolerable. TCR- T cells appeared in peripheral blood with cell-dose dependent manner.

<sec>
<title>Disclosures</title>
Fujiwara: Celgene: Honoraria, Other: Travel, Acomodations, Expenses. Akatsuka:Takara Bio. Inc.: Other: Advisor to the CAR project. Tomura:TAKARO BIO INC.: Employment. Nukaya:TAKARA BIO INC.: Employment. Takesako:TAKARA BIO INC.: Employment.

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B型肝炎キャリアの初回妊娠中に発症した重症再生不良性貧血(SAA)の1例

栗本恭好, 蟹江匡治, 岡本晃直, 稲熊容子, 徳田倍将, 柳田正光, 森島聡子, 山本幸也, 水田秀一, 赤塚美樹, 岡本昌隆, 恵美宣彦

臨床血液 2015年11月 (一社)日本血液学会-東京事務局

導入化学療法を受けない急性骨髄性白血病患者の転帰(The fate of patients with acute myeloid leukemia not undergoing induction chemotherapy)

Yanada Masamitsu, Okamoto Akinao, Inaguma Yoko, Tokuda Masutaka, Morishima Satoko, Kanie Tadaharu, Yamamoto Yukiya, Mizuta Shuichi, Akatsuka Yoshiki, Okamoto Masataka, Emi Nobuhiko

臨床血液 2015年9月 (一社)日本血液学会-東京事務局

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<赤塚 美樹>

講演・口頭発表等 - 赤塚 美樹

<赤塚　美樹>

講演・口頭発表等 - 赤塚　美樹