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Off-the-shelf immunotherapy with CAR-gamma delta T cells

Research Project

Project/Area Number 20K07674
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 50020:Tumor diagnostics and therapeutics-related
Research InstitutionMie University

Principal Investigator

Kato Takuma  三重大学, 医学系研究科, 准教授 (60224515)

Co-Investigator(Kenkyū-buntansha) 王 立楠  三重大学, 医学系研究科, 助教 (00589484)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsキメラ抗原受容体 / γδT細胞 / off-the-shelf / アロ反応性 / 移植片対宿主反応 / 抗酸化因子 / 疲弊抵抗性 / ミトコンドリア / 酸化ストレス / γδT細胞 / 癌胎児性抗原 / 膵臓癌
Outline of Research at the Start

①CEA陽性膵がん細胞を同所性に移植したマウスXenograftモデルを用いて、GITRL搭載CEA特異的CAR導入γδT細胞がGVHDを発症することなく腫瘍抑制効果を発揮する事を明らかにする。
②CEA以外のTAAに対する抗体の追加投与よる二重標的化によりCEA loss variantに対して抗腫瘍効果を発揮することを明らかにする。
③上述の抗腫瘍効果が、GITRシグナルによるγδT細胞のTreg抵抗性の獲得とTregの抑制活性の阻害に起因している可能性を明らかにする。
④輸注T細胞の質的・量的特性を明らかにする。

Outline of Final Research Achievements

Gamma/delta T cells were successfully transduced with a CAR specific to CEA with signaling domains of CD3zeta and CD28 (CEA.CAR-gd T cells). In a xenograft mouse model, CEA.CAR-gdT cells suppressed CEA+ tumor growth though a limited time window. Provision of GITR co-stimulation enhanced anti-tumor function of CEA.CAR-gd T cells, the result of which imposes additional measurers to be adopted in CAR-γδ T cells for an allogeneic adoptive immunotherapy. Therefore, CEA.CAR-gd T cells were prepared in the presence of NAC. NAC-pretreated CAR-T cells produced more IFN-g, enhanced serial killing function. These results suggest that supplementation of NAC during CAR-gd T cell preparation may be one of ways to obtain exhaustion resistant CAR-gdT cells which may have higher in vivo tumor control ability.

Academic Significance and Societal Importance of the Research Achievements

従来のCAR-Tでは、患者自身の末梢血からCAR-Tを調整するため、CAR-Tの質・量・均一性が安定せず、治療効果に大きな影響を及ぼす。さらに、病勢の進行した患者も含め、より多くの患者に対応するためには、調整時間を短くコストを下げなければならない。そこでアロ反応性を持たないγδ型T細胞を用いてCAR-Tを作製しoff-the-shelf化によるCAR-T輸注療法の適応拡大を目指した。その結果、CAR導入γδ型T細胞はCAR-T輸注療法の生物製剤としての有効性を示した。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (7 results)

All 2023 2022 2021

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (6 results)

  • [Journal Article] Tumor Growth Suppression of Pancreatic Cancer Orthotopic Xenograft Model by CEA-Targeting CAR-T Cells2023

    • Author(s)
      Osamu Sato, Takahiro Tsuchikawa , Takuma Kato , Yasunori Amaishi , Sachiko Okamoto, Junichi Mineno , Yuta Takeuchi , Katsunori Sasaki, Toru Nakamura, Kazufumi Umemoto, Tomohiro Suzuki, Linan Wang, Yizheng Wang, Kanako C Hatanaka , Tomoko Mitsuhashi , Yutaka Hatanaka , Hiroshi Shiku , Satoshi Hirano
    • Journal Title

      Cancers

      Volume: 15 Issue: 3 Pages: 1-18

    • DOI

      10.3390/cancers15030601

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] N-acetylcysteine renders CAR-T cells resistant to exhaustion for solid tumor immunotherapy2022

    • Author(s)
      Yizheng Wang, Yasunori Amaishi, Sachiko Okamoto, Junichi Mineino,Takuma Kato and Hiroshi Shiku
    • Organizer
      日本癌学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] N-acetylcysteine trigger exhaustion resistant CAR-T cell for solid tumor immunotherapy2022

    • Author(s)
      Yizheng Wang, Yasunori Amaishi, Sachiko Okamoto, Junichi Mineino,Takuma Kato and Hiroshi Shiku
    • Organizer
      日本がん免疫学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Energy metabolism of NY-ESO-1-specific αβ-TCR transduced γδ-T cells2022

    • Author(s)
      Mikiya Ishihara,Hiroshi Miwa, Yasushi Akahori, Hiroshi Fujiwara, Takuma Kato, Yoshimasa Tanaka Isao Tawara and Hiroshi Shiku
    • Organizer
      日本癌学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Energy metabolism spread to non-glycolysis in alpha/beta-TCR transduced gamma/delta-T cellsEnergy metabolism of NY-ESO-1-specific αβ-TCR transduced γδ-T cells2022

    • Author(s)
      Mikiya Ishihara,Hiroshi Miwa, Yasushi Akahori, Hiroshi Fujiwara, Takuma Kato, Yoshimasa Tanaka Isao Tawara and Hiroshi Shiku
    • Organizer
      日本がん免疫学会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Potential for the use of gene-modified Vγ9Vδ2 T cells for cancer immunotherapy2021

    • Author(s)
      Yizheng Wang, Linan Wang, Satoshi Okumura, Naohiro Seo, Sachiko Okamoto, Yasunori Amaishi, Junichi Mineno, Yoshimasa Tanaka, Takuma Kato and Hiroshi Shiku
    • Organizer
      日本サイトカイン・インターフェロン学会
    • Related Report
      2021 Research-status Report
  • [Presentation] Potential for the use of gene-modified Vγ9Vδ2 T cells for cancer immunotherapy2021

    • Author(s)
      Yizheng Wang, Linan Wang, Satoshi Okumura, Naohiro Seo, Sachiko Okamoto, Yasunori Amaishi, Junichi Mineno, Yoshimasa Tanaka, Takuma Kato and Hiroshi Shiku
    • Organizer
      日本癌学会
    • Related Report
      2021 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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