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Utilizing ageing-related clonal haematopoesisfor effective CAR-T cell therapy

Research Project

Project/Area Number 22K19474
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 50:Oncology and related fields
Research InstitutionKeio University (2023)
Aichi Cancer Center Research Institute (2022)

Principal Investigator

Inoue Satoshi  慶應義塾大学, 医学部(信濃町), 講師 (30801930)

Project Period (FY) 2022-06-30 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2023: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2022: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
KeywordsCAR-T細胞 / 加齢 / ゲノム異常 / CAR=T細胞 / クローン造血 / クローン性造血
Outline of Research at the Start

本研究では、加齢に伴い末梢血T細胞において蓄積される遺伝子変異を同定し、これらの変異遺伝子を野生型T細胞に付加することにより、その長期生存能を高め、同細胞から作製される抗腫瘍T細胞が持続的な治療効果を誘導できるという仮説を立て、以下の研究を進める。
①末梢血T細胞における加齢に伴う遺伝子変異を検出する
②加齢に伴う遺伝子変異(群)が正常T細胞機能の長期生存能に寄与することを示す。
③個々の変異遺伝子がCAR-T細胞機能に及ぼす性質変化を分子レベルで解明する。

Outline of Final Research Achievements

We identified TET2, DNMT3A, and DUSP11 as aging-associated genetic mutations. First, we performed genetical ablabations of TET2, DNMT3A, and DUSP11 genes using the CRISPR Cas9 approach and analyzed the effects on the function of T cells and CAR-T cells. T cells or CAR-T cells with knockout of TET2 or DNMT3A genes indeed exhibited significant promotion of undifferentiated state (persistence),in agreement with previous reports. However, T cells and CAR-T cells with DUSP11 gene knockout did not show promotion of undifferentiated state (long-term survival capacity) as observed with TET2 or DNMT3A knockout T cells. Furthermore, no effects were observed on cell proliferation, cytokine and cytotoxic factor production, or cytotoxicity (anti-tumor effect). So far, we were unable to identify aging-related mutations that would favorably impact CAR-T cell immunotherapy.

Academic Significance and Societal Importance of the Research Achievements

近年の正常部ゲノム解析により、多くの正常組織において、加齢によって体細胞変異が蓄積した細胞の一部が分化能を喪失したクローン性増殖能を獲得し、最終的に悪性化腫瘍を発症することが明らかになったが、これらは加齢によって発生する「前がん病変」を捉えることを目的とした研究であり、治療法に活用させることを意図した研究は皆無である。
本研究は、加齢に伴いT細胞で蓄積する、腫瘍化につながり得る遺伝子変異を逆にCAR-T細胞療法の治療効果改善に活用することを目指す、という新しい着想に基づく研究計画であり、既存の治療戦略の延長線にのらない治療法である。

Report

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

    (5 results)

All 2024 2023 2022

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

  • [Journal Article] Gene editing technology to improve antitumor T-cell functions in adoptive immunotherapy2024

    • Author(s)
      Ito Y, Inoue S, Kagoya Y.
    • Journal Title

      Inflamm Regen .

      Volume: 44 Issue: 1 Pages: 13-13

    • DOI

      10.1186/s41232-024-00324-7

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] High CD62L expression predicts the generation of chimeric antigen receptor T cells with potent effector functions2024

    • Author(s)
      Kasuya H, Zhang H, Ito Y, Yoshikawa T, Nakashima T, Li Y, Matsukawa T, Inoue S, Kagoya Y
    • Journal Title

      Int Immunol .

      Volume: ー Issue: 7 Pages: 353-364

    • DOI

      10.1093/intimm/dxae015

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] CD83 expression characterizes precursor exhausted T cell population2023

    • Author(s)
      Wu Zhiwen、Yoshikawa Toshiaki、Inoue Satoshi、Ito Yusuke、Kasuya Hitomi、Nakashima Takahiro、Zhang Haosong、Kotaka Saki、Hosoda Waki、Suzuki Shiro、Kagoya Yuki
    • Journal Title

      Communications Biology

      Volume: 6 Issue: 1 Pages: 258-258

    • DOI

      10.1038/s42003-023-04631-6

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Epigenetic profiles guide improved CRISPR/Cas9-mediated gene knockout in human T cells2023

    • Author(s)
      Ito Yusuke、Inoue Satoshi、Nakashima Takahiro、Zhang Haosong、Li Yang、Kasuya Hitomi、Matsukawa Tetsuya、Wu Zhiwen、Yoshikawa Toshiaki、Kataoka Mirei、Ishikawa Tetsuo、Kagoya Yuki
    • Journal Title

      Nucleic Acids Research

      Volume: 52 Issue: 1 Pages: 141-153

    • DOI

      10.1093/nar/gkad1076

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetic ablation of PRDM1 in antitumor T cells enhances therapeutic efficacy of adoptive immunotherapy2022

    • Author(s)
      Toshiaki Yoshikawa, Zhiwen Wu, Satoshi Inoue, Hitomi Kasuya, Hirokazu Matsushita, Yusuke Takahashi, Hiroaki Kuroda, Waki Hosoda, Shiro Suzuki, Yuki Kagoya
    • Journal Title

      Blood

      Volume: 139 Issue: 14 Pages: 2156

    • DOI

      10.1182/blood.2021012714

    • URL

      https://pure.teikyo.jp/en/publications/6a2b019c-e097-4984-a55e-185c8e982370

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access

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Published: 2022-07-05   Modified: 2025-01-30  

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