Optimization of chimeric antigen receptor-gene modified T lymphocyte generation

• Project/Area Number: 24790969
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Nagoya University
• Principal Investigator: TERAKURA Seitaro 名古屋大学, 医学部附属病院, 病院助教 (40625141)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: キメラ抗原レセプター / 細胞療法 / 遺伝子導入T細胞 / 免疫療法 / リンパ性白血病 / 悪性リンパ腫 / 遺伝子導入T細胞療法 / CD8陽性Tリンパ球 / Tリンパ球 / CD8陽性

Outline of Final Research Achievements

We aimed to optimize the method for generation of chimeric antigen receptor-gene modified T lymphocyte (CD19CAR-T). For the generation of allogeneic CD19CAR-T lymphocytes, we analyzed the method for better generation of virus-specific/ CD19CAR-gene modified T lymphocytes. We tested the possible combination of cytokine combination and concentration. As a result, the IL-2 and IL-21 combination was better than other conditions. For the optimization of autologous CD19CAR-T lymphocytes, we developed drug-inducible expression system of CD19CAR, and demonstrated that we could successfully control CD19CAR expression under drug administration.

Research Products

• [Journal Article] Target antigen density governs the efficacy of anti-CD20-CD28-CD3 ζ chimeric antigen receptor-modified effector CD8+ T cells. (2015)
  • Author(s): Watanabe K, Terakura S, Martens AC, van Meerten T, Uchiyama S, Imai M, Sakemura R, Goto T, Hanajiri R, Imahashi N, Shimada K, Tomita A, Kiyoi H, Nishida T, Naoe T, Murata M.
  • Journal Title: J Immunol. Volume: 194(3) Issue: 3 Pages: 911-20
  • DOI: 10.4049/jimmunol.1402346
  • Peer Reviewed
• [Journal Article] Simple and Efficient Generation of Virus-specific T Cells for Adoptive Therapy Using Anti-4-1BB Antibody (2015)
  • Author(s): Nobuhiko Imahashi, Tetsuya Nishida, Tatsunori Goto, Seitaro Terakura, Keisuke Watanabe, Ryo Hanajiri, Reona Sakemura, Misa Imai, Hitoshi Kiyoi, Tomoki Naoe, and Makoto Murata
  • Journal Title: Journal of Immunotherapy Volume: 38(2) Issue: 2 Pages: 62-70
  • DOI: 10.1097/cji.0000000000000069
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Chimerism status after unrelated donor bone marrow transplantation with fludarabine-melphalan conditioning is affected by the melphalan dose and is predictive of relapse. (2015)
  • Author(s): Imahashi N, Ohashi H, Terakura S, Miyao K, Sakemura R, Kato T, Sawa M, Yokohata E, Kurahashi S, Ozawa Y, Nishida T, Kiyoi H, Watamoto K, Kohno A, Kasai M, Kato C, Iida H, Naoe T, Miyamura K, Murata M
  • Journal Title: Annals of Hematology Volume: -
  • Peer Reviewed
• [Journal Article] Successful unrelated cord blood transplantation for adult acquired aplastic anemia using reduced intensity conditioning without ATG. (2014)
  • Author(s): Terakura S, Nishida T, Inamoto Y, Ohashi H, Naoe T, Murata M.
  • Journal Title: Immunology Letters Volume: - Issue: 1 Pages: 99-101
  • DOI: 10.1016/j.imlet.2014.01.013
  • Peer Reviewed
• [Journal Article] Dexamethasone palmitate ameliorates macrophages-rich graft-versus-host disease by inhibiting macrophage functions (2014)
  • Author(s): Satoshi Nishiwaki, Takayuki Nakayama, Makoto Murata, Tetsuya Nishida, Seitaro Terakura, Shigeki Saito, Tomonori Kato, Hiroki Mizuno, Nobuhiko Imahashi, Aika Seto, Yukiyasu Ozawa, Koichi Miyamura, Masafumi Ito, Kyosuke Takeshita, Hidefumi Kato, Shinya Toyokuni, Keisuke Nagao, Ryuzo Ueda, and Tomoki Naoe
  • Journal Title: PLOS one Volume: 9(5) Issue: 5 Pages: e96252-e96252
  • DOI: 10.1371/journal.pone.0096252
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of cord blood transplantation with unrelated bone marrow transplantation in patients older than fifty years. (2014)
  • Author(s): Tanaka M, Miyamura K, Terakura S, Imai K, Uchida N, Ago H, Sakura T, Eto T, Ohashi K, Fukuda T, Taniguchi S, Mori S, Nagamura-Inoue T, Atsuta Y, Okamoto S.
  • Journal Title: Biol Blood Marrow Transplant. Volume: 21 Issue: 3 Pages: 517-525
  • DOI: 10.1016/j.bbmt.2014.11.685
  • Peer Reviewed
• [Journal Article] Randomized controlled trial comparing ciprofloxacin and cefepime in febrile neutropenic patients with hematological malignancies. (2013)
  • Author(s): Yasuda T
  • Journal Title: Int J Infect Dis. Volume: 17 Issue: 6 Pages: e385-e390
  • DOI: 10.1016/j.ijid.2012.12.005
  • Peer Reviewed
• [Journal Article] Identification of a novel HLA-A^*24:02-restricted adenovirus serotype 11-specific CD8+ T-cell epitope for adoptive immunotherapy (2013)
  • Author(s): Imahashi N, Nishida T, Ito Y, Kawada J, Nakazawa Y, Toji S, Suzuki S, Terakura S, Kato T, Murata M, Naoe T.
  • Journal Title: Molecular Immunolgy Volume: 56 Issue: 4 Pages: 399-405
  • DOI: 10.1016/j.molimm.2013.05.232
  • Peer Reviewed
• [Journal Article] Unrelated cord blood transplantation vs related transplantation with HLA 1-antigen mismatch in the graft-versus-host direction (2013)
  • Author(s): Kanda J, Ichinohe T, Kato S, Uchida N, Terakura S, et al.
  • Journal Title: Leukemia Volume: 27 Issue: 2 Pages: 286-294
  • DOI: 10.1038/leu.2012.203
  • Peer Reviewed
• [Journal Article] Phase II study of dose-modified busulfan by real-time targeting in allogeneic hematopoietic stem cell transplantation for myeloid malignancy. (2012)
  • Author(s): Kuwatsuka Y, Kohno A, Terakura S, Saito S, Shimada K, Yasuda T, Inamoto Y, Miyamura K, Sawa M, Murata M, et al.
  • Journal Title: Cancer Science Volume: 103 Issue: 9 Pages: 1688-1694
  • DOI: 10.1111/j.1349-7006.2012.02342.x
  • Peer Reviewed
• [Journal Article] Escape of leukemia blasts from HLA-specific CTL pressure in a recipient of HLA one locus-mismatched bone marrow transplantation. (2012)
  • Author(s): Kato T, Terakura S, Murata M, Sugimoto K, Murase M, Iriyama C, Tomita A, Abe A, Suzuki M, Nishida T, Naoe T.
  • Journal Title: Cellular Immunology Volume: 276 Issue: 1-2 Pages: 75-82
  • DOI: 10.1016/j.cellimm.2012.03.011
  • Peer Reviewed
• [Journal Article] Generation of CD19-chimeric antigen receptor modified CD8+ T cells derived from virus-specific central memory T cells (2012)
  • Author(s): Terakura S, Yamamoto TN, Gardner RA, Turtle CJ, Jensen MC, Riddell SR
  • Journal Title: Blood Volume: 119(1) Issue: 1 Pages: 72-82
  • DOI: 10.1182/blood-2011-07-366419
  • Peer Reviewed
• [Presentation] 40-55歳に対するリン酸フルダラビンとメルファランを前処置とした非血縁間骨髄移植の有用性 (2015)
  • Author(s): 渡邊慶介、澤正史、河野彰夫、飯田浩充、内田俊樹、大西康、大橋春彦、熱田由子、鈴木律朗、寺倉精太郎、西田徹也、村田誠、宮村耕一、森下 剛久
  • Organizer: 第37回日本造血細胞移植学会総会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-03-05 – 2015-03-07
• [Presentation] 非血縁骨髄移植後のキメリズム状態は前治療強度に影響され、再発の予測因子となりうる (2015)
  • Author(s): 寺倉精太郎、今橋伸彦、大橋春彦、宮尾康太郎、酒村玲央奈、澤正史、横畠恵美、倉橋信悟、小澤幸泰、西田徹也、清井仁、綿本浩一、河野彰夫、笠井雅信、加藤千明、飯田浩充、宮村耕一、村田誠
  • Organizer: 第37回日本造血細胞移植学会総会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-03-05 – 2015-03-07
• [Presentation] Excessively High-Affinity Single-Chain Fragment Variable Region in a Chimeric Antigen Receptor Can Counteract T-Cell Proliferation (2014)
  • Author(s): Watanabe K, Terakura S, Uchiyama S, Martens AC, van Meerten T, Nishida T, Naoe T, Kiyoi H, Murata M
  • Organizer: 第56回米国血液学会
  • Place of Presentation: サンフランシスコ、米国
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Comparison of outcomes of unrelated BM and CB transplants in young adult leukemia patients. An Updated Results of Japanese Registration Data (2014)
  • Author(s): Terakura S, Atsuta Y, Tsukada N, Kobayashi T, Tanaka M, Kanda J, Ohashi K, Fukuda T, Uchida N, Takahashi S, Nagamura-Inoue T, Morishima Y, Miyamura K
  • Organizer: 第56回米国血液学会
  • Place of Presentation: サンフランシスコ、米国
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Comparison of unrelated bone marrow and umbilical cord blood transplants in young adult leukemia (2014)
  • Author(s): 寺倉精太郎、熱田由子、塚田信弘、小林武、田中正嗣、諫田淳也、大橋一輝、福田隆浩、内田直之、高橋聡、長村登紀子、森島泰雄、宮村耕一
  • Organizer: 第76回日本血液学会総会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] Anti-CD20 chimeric antigen receptor+ T cells can recognize remarkably low target antigen expression (2014)
  • Author(s): 渡邊慶介、寺倉精太郎、内山進、今井美沙、酒村玲央奈、後藤辰徳、葉名尻良、島田和之、西田徹也、直江知樹、冨田章裕、清井仁、村田誠
  • Organizer: 第76回日本血液学会総会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] キメラ抗原レセプター遺伝子導入T細胞を用いた細胞治療の今後 (2014)
  • Author(s): 寺倉精太郎
  • Organizer: 第63回日本輸血・細胞治療学会東海支部例会
  • Place of Presentation: 名古屋第一赤十字病院（愛知県名古屋市）
  • Year and Date: 2014-09-20
  • Invited
• [Presentation] キメラ抗原受容体単鎖抗体部分の強すぎる親和性は抗原刺激後のT細胞増殖を阻害する (2014)
  • Author(s): 渡邊慶介、寺倉精太郎、今井美沙、酒村玲央奈、後藤辰徳、葉名尻良、今橋伸彦、島田和之、冨田章裕、西田徹也、村田誠、清井仁
  • Organizer: 第6回血液疾患免疫療法研究会学術集会
  • Place of Presentation: 京都国際会議場（京都府京都市）
  • Year and Date: 2014-09-06
• [Presentation] 新規CD20キメラ抗原レセプターの開発～CD20低発現標的細胞に対する効果
  • Author(s): 寺倉精太郎
  • Organizer: 第14回基礎血液懇話会
  • Place of Presentation: 名古屋大学大学院医学系研究科 (名古屋市)
• [Presentation] 新規CD20キメラ抗原レセプター遺伝子導入T細胞の樹立とCD20低発現標的に対する効果の検討
  • Author(s): 渡邊慶介、寺倉精太郎、後藤辰徳、葉名尻良、今橋伸彦、西田徹也、村田誠、直江知樹
  • Organizer: 第５回造血器腫瘍免疫療法研究会
  • Place of Presentation: アイリス名古屋 (名古屋市)
• [Presentation] Cord blood allograft rejection mediated by coordination of cellular and humoral immunity
  • Author(s): Ryo Hanajiri, Makoto Murata, Kyoko Sugimoto, Miho Murase, Haruhiko Ohashi, Tatsunori Goto, Keisuke Watanabe, Nobuhiko Imahashi, Seitaro Terakura, Tetsuya Nishida, Tomoki Naoe
  • Organizer: 第75回日本血液学会
  • Place of Presentation: 札幌芸文館 （札幌市)
• [Presentation] Identification of a novel HLA-A*2402-restricted adenovirus serotype 11-specific CD8+ T-cell epitope
  • Author(s): Nobuhiko Imahashi, Tetsuya Nishida, Yoshinori Ito, Jun-Ichi Kawada, Yozo Nakazawa, Shingo Toji, Susumu Suzuki, Seitaro Terakura, Tomonori kato, Makoto Murata, Tomoki Naoe
  • Organizer: 第75回日本血液学会
  • Place of Presentation: 札幌市教育文化会館 (札幌市)
• [Presentation] Anti-CD20 Chimeric Antigen Receptor Transduced T Cells Can Recognize Very Low Antigen Expression: Determination Of The Lower Threshold Required To Activate The CAR-T Cells
  • Author(s): Keisuke Watanabe, Seitaro Terakura, Tatsunori Goto, Ryo Hanajiri, Nobuhiko Imahashi, Kazuyuki Shimada, Tetsuya Nishida, Akihiro Tomita, Makoto Murata, Tomoki Naoe
  • Organizer: 第55回米国血液学会総会
  • Place of Presentation: New Orleans, USA
• [Presentation] Cord Blood Allograft Rejection Mediated By Coordinated Donor-Specific Cellular and Humoral Immune Processes
  • Author(s): Ryo Hanajiri, Makoto Murata, Kyoko Sugimoto, Miho Murase, Haruhiko Ohashi, Tatsunori Goto, Keisuke Watanabe, Nobuhiko Imahashi, Seitaro Terakura, Tetsuya Nishida, Tomoki Naoe
  • Organizer: 第55回米国血液学会総会
  • Place of Presentation: New Orleans, USA
• [Presentation] Impact of Macrophage Activation on Delayed Engraftment Following Allogeneic Hematopoietic Stem Cell Transplantation: Mac Ratio, a New Predictive Index
  • Author(s): Naomi Kawashima, Satoshi Nishiwaki, Seitaro Terakura, Sonoko Kamoshita, Kyoko Watakabe, Emi Yokohata, Daisuke Koyama, Naoko Shimizu, Shingo Kurahashi, Yukiyasu Ozawa, Masafumi Ito, Koichi Miyamura
  • Organizer: 第55回米国血液学会総会
  • Place of Presentation: New Orleans, USA
• [Presentation] 同種臍帯血移植を行い良好な生着・生存を得た成人再生不良性貧血の3例
  • Author(s): 寺倉精太郎、後藤辰徳、葉名尻良、渡邊慶介、今橋伸彦、西田徹也、村田誠、直江知樹
  • Organizer: 第36回日本造血細胞移植学会
  • Place of Presentation: 沖縄コンベンションセンター (那覇市)
• [Presentation] 新規CD20キメラ抗原レセプター遺伝子導入T細胞の樹立とCD20低発現標的に対する効果の検討
  • Author(s): 渡邊慶介、寺倉精太郎、後藤辰徳、葉名尻良、今橋伸彦、西田徹也、村田誠、直江知樹
  • Organizer: 第36回日本造血細胞移植学会
  • Place of Presentation: 沖縄コンベンションセンター (那覇市)
• [Presentation] 臍帯血移植片拒絶症例におけるドナーHLA特異的抗体とドナーHLA特異的細胞傷害性T細胞の協働作用
  • Author(s): 葉名尻良、村田誠、杉本恭子、村瀬未帆、大橋春彦、後藤辰徳、渡邊慶介、今橋伸彦、寺倉精太郎、西田徹也、直江知樹
  • Organizer: 第36回日本造血細胞移植学会
  • Place of Presentation: 沖縄コンベンションセンター (那覇市)
• [Presentation] Fludarabine+Cyclophosphamideを用いた減量強度前処置による多発性骨髄腫に対する同種造血細胞移植の検討
  • Author(s): 後藤辰徳、齊藤繁紀、寺倉精太郎、西田徹也、冨田章裕、村田誠、直江知樹
  • Organizer: 第36回日本造血細胞移植学会
  • Place of Presentation: 沖縄コンベンションセンター (那覇市)
• [Presentation] 非血縁者間骨髄移植後難治性CMV感染に対してCMV抗原特異的CTLが著効した2症例
  • Author(s): 西田徹也、村田誠、寺倉精太郎、勝見章、直江知樹
  • Organizer: 第36回日本造血細胞移植学会
  • Place of Presentation: 沖縄コンベンションセンター (那覇市)
• [Presentation] セントラル・メモリーT細胞由来、ウイルス特異的/CD19特異的キメラ抗原レセプター遺伝子導入T細胞の作成
  • Author(s): 寺倉精太郎
  • Organizer: 第4回造血器腫瘍免疫療法研究会
  • Place of Presentation: 金沢市文化ホール (金沢市)
• [Book] 血液疾患 最新の治療 2014-2016 巻頭トピックス8 新しい細胞免疫療法の進展 (2014)
  • Author(s): 寺倉精太郎、直江知樹、小澤敬也、中尾眞二
  • Publisher: 南江堂
• [Patent(Industrial Property Rights)] ヒト化抗CD20キメラ抗原レセプター (2013)
  • Inventor(s): 寺倉精太郎、渡邊慶介
  • Industrial Property Rights Holder: 名古屋大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-234784
  • Filing Date: 2013-11-13