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Generation of long-surviving antitumor T cells by genetic modification for optimal adoptive immunotherapy

Research Project

Project/Area Number 20H03543
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 50020:Tumor diagnostics and therapeutics-related
Research InstitutionAichi Cancer Center Research Institute

Principal Investigator

Kagoya Yuki  愛知県がんセンター(研究所), 腫瘍免疫応答研究分野, 客員研究員 (70706960)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000)
Fiscal Year 2022: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2021: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2020: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Keywords養子免疫療法 / 悪性腫瘍 / メモリーT細胞 / キメラ抗原受容体 / エピジェネティック因子 / 転写制御因子 / T細胞疲弊 / 抗腫瘍T細胞 / 遺伝子変異 / T細胞性リンパ腫 / エピジェネティクス / 転写因子 / CRISPR/Cas9
Outline of Research at the Start

抗腫瘍T細胞の長期生存能を高めるために、本研究ではT細胞性リンパ腫細胞で変異が報告されている遺伝子群に着目する。これらの遺伝子を個別に抗腫瘍T細胞に導入してその機能(増殖能、サイトカイン分泌、細胞傷害活性など)を解析することで、長期生存能・持続的抗腫瘍効果に関わる標的遺伝子候補を同定する。次に同定した遺伝子(群)の修飾によるT細胞の遺伝子発現・エピジェネティックプロファイル変化を解析し、機能変化を引き起こす分子機構の解明を目指す。最後に遺伝子改変を加えた抗腫瘍T細胞が複数のin vivoマウス腫瘍モデルにおいて優れた治療効果を有することを示す。

Outline of Final Research Achievements

The overarching goal of this study is to enhance therapeutic efficacy of adoptive cancer immunotherapy, in which tumor antigen-specific T cells are prepared in vitro and infused back into the patient. We aimed to improve long-surviving capacity of antitumor T cells through genetic engineering. We further addressed molecular mechanisms of how modification of the identified target(s) affects T cell longevity.
We identified multiple targets associated with self-renewal proliferation of T cells. Especially, genetic ablation of the transcription factor PRDM1, which encodes Blimp1, significantly improved persistence of antitumor T cells. We confirmed that Blimp1-deficient T cells can induce durable antitumor response using multiple mouse tumor models. In addition to these findings, we analyzed molecular profiles of exhausted T cells in detail and identified that the expression of CD83 marks precursor exhausted T cells, which will be useful to finely dissect dysfunctional T cells.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、がんに対する養子免疫療法、例えば現在血液腫瘍に対して実臨床で用いられているキメラ抗原受容体 (CAR)導入T細胞療法などの治療効果を高めることへの応用性を持つ。CAR-T細胞は一過性には治療効果が高いが、その後の再発などで持続的な治療効果が得られる症例は限定的であることから、輸注されたT細胞の長期生存能を高めることで、治癒を目指した治療法開発が可能となる。また免疫チェックポイント阻害剤をはじめとするがん免疫療法では、治療効果を予測するバイオマーカー探索が重要であり、長期生存能に優れた前駆疲弊分画をマークするCD83分子に関する知見は有効性予測に寄与する可能性がある。

Report

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

    (23 results)

All 2023 2022 2021 2020

All Journal Article (3 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 3 results,  Open Access: 2 results) Presentation (20 results) (of which Int'l Joint Research: 5 results,  Invited: 18 results)

  • [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
      2022 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 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetic Ablation of HLA Class I, Class II, and the T-cell Receptor Enables Allogeneic T Cells to Be Used for Adoptive T-cell Therapy2020

    • Author(s)
      Kagoya Yuki、Guo Tingxi、Yeung Brian、Saso Kayoko、Anczurowski Mark、Wang Chung-Hsi、Murata Kenji、Sugata Kenji、Saijo Hiroshi、Matsunaga Yukiko、Ohashi Yota、Butler Marcus O.、Hirano Naoto
    • Journal Title

      Cancer Immunology Research

      Volume: 8 Issue: 7 Pages: 926-936

    • DOI

      10.1158/2326-6066.cir-18-0508

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] エピジェネティック機構の制御による抗腫瘍T細胞の改変2022

    • Author(s)
      籠谷 勇紀
    • Organizer
      第81回日本癌学会学術総会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 次世代型CAR-T細胞療法の開発2022

    • Author(s)
      籠谷 勇紀
    • Organizer
      第6回バイオ医薬EXPO
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] CAR-T 細胞療法の適用拡大に 向けた研究開発2022

    • Author(s)
      籠谷 勇紀
    • Organizer
      第7回日本がんサポーティブケア学会学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] エピジェネティクス改変による長期生存型CAR-T細胞の製造2022

    • Author(s)
      籠谷 勇紀
    • Organizer
      第14回日本血液疾患免疫療法学会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Synthetic immunology to enhance safety and efficacy in adoptive cancer immunotherapy2022

    • Author(s)
      籠谷 勇紀
    • Organizer
      第51回日本免疫学会学術集会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] エピジェネティクス修飾によるCAR-T細胞の改良2022

    • Author(s)
      籠谷 勇紀
    • Organizer
      第3回東京理科大学総合研究院合成生物学研究部門シンポジウム
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Genetic modification of antitumor T cells for optimal adoptive cancer immunotherapy2022

    • Author(s)
      Yuki Kagoya
    • Organizer
      Franco-Japanese immuno-oncology webinars series
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Memory Response of Gene Therapy Product; in View of Biodistribution2021

    • Author(s)
      Yuki Kagoya
    • Organizer
      6th DIA Cell and Gene Therapy Products Symposium in Japan
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Future perspectives of CAR-T cell therapy for cancer2021

    • Author(s)
      Yuki Kagoya
    • Organizer
      The 25th JFCR-ISCC
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Redefining T cell exhaustion - Understanding T cell states at molecular levels2021

    • Author(s)
      籠谷 勇紀
    • Organizer
      第50回日本免疫学会学術集会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 転写ネットワーク修飾による T細胞機能の改変2021

    • Author(s)
      籠谷 勇紀
    • Organizer
      第94回日本生化学大会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 次世代CART細胞療法の開発動向2021

    • Author(s)
      籠谷 勇紀
    • Organizer
      BioJapan 2021
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Epigenetic and metabolic modification of CAR-T cells for optimal adoptive immunotherapy2021

    • Author(s)
      Yuki Kagoya
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Epigenetic modification of antitumor T cells for optimal adoptive immunotherapy2021

    • Author(s)
      吉川 聡明, 呉 智聞, 松下 博和,細田 和貴, 鈴木 史朗, 籠谷 勇紀
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Epigenetic insights into T cell longevity for optimal adoptive immunotherapy2021

    • Author(s)
      Yuki Kagoya
    • Organizer
      JCA-AACR Precision Cancer Medicine International Conference
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Epigenetic modification of antitumor T cells to induce durable clinical response in adoptive immunotherapy2021

    • Author(s)
      吉川 聡明, 呉 智聞, 松下 博和, 細田 和貴, 鈴木 史朗, 籠谷 勇紀
    • Organizer
      第25回日本がん免疫学会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 抗腫瘍T細胞の機能評価を行う上でのポイント2021

    • Author(s)
      籠谷 勇紀
    • Organizer
      日本再生医療学会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 合成生物学による免疫細胞療法の改良2020

    • Author(s)
      籠谷 勇紀
    • Organizer
      日本輸血・細胞治療学会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 免疫工学によるCAR-T細胞の改良開発2020

    • Author(s)
      籠谷 勇紀
    • Organizer
      血液疾患免疫療法学会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] Epigenetic modification of CAR-T cells for optimal adoptive immunotherapy,2020

    • Author(s)
      籠谷 勇紀
    • Organizer
      第79回日本癌学会学術集会
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research / Invited

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

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