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Conversion of exhausted CAR T cells into stem-like CAR T cells to treat solid tumors

Research Project

Project/Area Number 22K20778
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0803:Pathology, infection/immunology, and related fields
Research InstitutionKeio University

Principal Investigator

ANDO Makoto  慶應義塾大学, 医学部(信濃町), 助教 (60962222)

Project Period (FY) 2022-08-31 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsCAR T細胞 / 疲弊T細胞 / ステムセルメモリーT細胞 / CAR T細胞療法 / がん免疫療法 / T細胞疲弊 / CAR T療法
Outline of Research at the Start

がん免疫の主体である細胞傷害性CD8+T細胞はがん微小環境化で、慢性的な抗原刺激によって疲弊化し抗腫瘍効果が減弱する。CAR-T細胞療法は血液がんでは大きな成果が得られたが、疲弊化に起因する治療効果の低下により固形がんに対しては未だ効果が認められない。一方、幹細胞様メモリーT(TSCM)細胞は最も幼若なメモリーT細胞で、増殖能や長期生存能に優れており強力な抗腫瘍活性を有する。本研究では、疲弊抵抗性CAR-T細胞の作製と、完全に疲弊化したT細胞から若いTSCM様細胞への誘導法を開発し、固形がん治療への応用を目指す。

Outline of Final Research Achievements

Loss of stemness and exhaustion of CAR T cells are major obstacles to CAR T cell therapy targeting solid tumors. We focused on the exhaustion and stemness in CAR T cells to address these issues and developed a method for reprogramming CAR T cells into stem-like CAR T cells. In this study, we found that gene transfer of dominant-negative NR4A enhanced the antitumor activity of CAR T cells. On the other hand, we found that the stem-like program of CAR T cells is regulated by FOXO1. In conclusion, inhibiting the function of the exhaustion factor NR4A and regulating the activity of the stem-like factor FOXO1 are promising strategies for the development of CAR T cell therapy targeting solid tumors.

Academic Significance and Societal Importance of the Research Achievements

CAR T 細胞療法は抗癌剤耐性の白血病患者に対して強い治療効果を示し、期待されているT 細胞移入療法であるが、固形がん患者に対しては未だ十分な治療効果が認められていない。本研究では、今まで不明であったCAR T細胞の運命を左右する転写因子として、FOXO1を同定した。さらに、疲弊因子NR4Aの機能阻害および幹細胞性因子FOXO1の活性増加による抗腫瘍活性の増加には、ミトコンドリア代謝リプログラミングが重要であることが明らかとなった。これらを同時に調節できれば、より効果的なCAR T細胞療法として未だ達成されていない固形がんを標的としたCAR T細胞療法への応用も期待できる。

Report

(3 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • Research Products

    (7 results)

All 2024 2023 2022

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 2 results) Presentation (5 results)

  • [Journal Article] NR4a1/2 deletion promotes accumulation of TCF1+ stem-like precursors of exhausted CD8+ T cells in the tumor microenvironment2024

    • Author(s)
      Srirat Tanakorn、Hayakawa Taeko、Mise-Omata Setsuko、Nakagawara Kensuke、Ando Makoto、Shichino Shigeyuki、Ito Minako、Yoshimura Akihiko
    • Journal Title

      Cell Reports

      Volume: 43 Issue: 3 Pages: 113898-113898

    • DOI

      10.1016/j.celrep.2024.113898

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] SOCS3 deletion in effector T?cells confers an anti-tumorigenic role of IL-6 to the pro-tumorigenic cytokine2023

    • Author(s)
      Mise-Omata Setsuko、Ando Makoto、Srirat Tanakorn、Nakagawara Kensuke、Hayakawa Taeko、Iizuka-Koga Mana、Nishimasu Hiroshi、Nureki Osamu、Ito Minako、Yoshimura Akihiko
    • Journal Title

      Cell Reports

      Volume: 42 Issue: 8 Pages: 112940-112940

    • DOI

      10.1016/j.celrep.2023.112940

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] “CAR T cell rest”によるTSCM様CAR T細胞の誘導と固形がん治療への応用2023

    • Author(s)
      安藤 眞
    • Organizer
      第33回 Kyoto T Cell Conference
    • Related Report
      2023 Annual Research Report
  • [Presentation] Reprogramming of exhausted CAR-T cells by " T cell rest”2022

    • Author(s)
      安藤 眞
    • Organizer
      JSICR/MMCB 2022 Joint Symposium
    • Related Report
      2022 Research-status Report
  • [Presentation] ”CAR T cell rest” による 疲弊 CAR-T 細胞のリプログラミング2022

    • Author(s)
      安藤 眞
    • Organizer
      第43回 日本炎症・再生医学会
    • Related Report
      2022 Research-status Report
  • [Presentation] Exhaustion-resistant CAR-T cells by overexpressing dominant negative form of NR4A factors for the treatment of solid tumors2022

    • Author(s)
      安藤 眞
    • Organizer
      The 51th Annual Meeting of the Japanese Society for Immunology
    • Related Report
      2022 Research-status Report
  • [Presentation] Antitumor efficacy of NR4a knock out HER2 CAR T-cell therapy for solid tumors2022

    • Author(s)
      中川原 賢亮
    • Organizer
      The 51th Annual Meeting of the Japanese Society for Immunology
    • Related Report
      2022 Research-status Report

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Published: 2022-09-01   Modified: 2025-01-30  

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