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Generation of universal donor cell souse for adoptive T cell therapy using iPSC technology

Research Project

Project/Area Number 19K23863
Research Category

Grant-in-Aid for Research Activity Start-up

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

Principal Investigator

Wang Bo  京都大学, iPS細胞研究所, 研究員 (80842765)

Project Period (FY) 2019-08-30 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsiPSC derived T cells / immune rejection / gene editing / iPSC-derived T cells / iPSCs / Activated iPS-T cells / PVR / adoptive T cells therapy
Outline of Research at the Start

To generate a “universal” iPS cell source for T cells toward following steps: (1) generate HLA Class I null iPSC by targeting the gene B2M, which is required for HLA calss I presentation on the cell surface. (2) generate HLA Class II null iPSC by knocking out their transactivator, CIITA, which must be a matter to allo-CD4 T cells since activated T cells naturally express HLA-II. (3) Express a defined NK cell inhibitory ligand, HLA-E to inhibit NK cells. (4) Selected deleting the NK cell activating ligands to decrease the factors which activate NK cells.

Outline of Final Research Achievements

Avoiding the immune rejection of transplanted T cells is central to the success of allogeneic cancer immunotherapies. One solution to protecting T-cell grafts from immune rejection involves the deletion of allogeneic factors and of factors that activate cytotoxic immune cells. Here we report the generation of hypoimmunogenic T cells derived from induced pluripotent stem cells (iPSCs) lacking β2-microglobulin, the class-II major histocompatibility complex (MHC) transactivator and the natural killer (NK) cell-ligand poliovirus receptor PVR, and expressing single-chain MHC class-I antigen E. In mouse models of CD20-expressing leukaemia or lymphoma, differentiated T cells expressing a CD20 chimeric antigen receptor largely escaped recognition by NKG2A+ and DNAM-1+ NK cells and by CD8 and CD4 T cells in the allogeneic recipients while maintaining anti-tumour potency. Hypoimmunogenic iPSC-derived T cells may contribute to the creation of off-the-shelf T cell immunotherapies.

Academic Significance and Societal Importance of the Research Achievements

ユニバーサルなT細胞免疫療法を目指してT細胞に直接ゲノム編集を行うさまざまな研究が行われてきましたが、ゲノム編行うことでT細胞の能力が弱まる可能性がある。本研究はこの問題を解決する方法として、iPS細胞の段階でゲノム編集を行い、それを分化させることでT細胞の弱体化を防ぎ、かつレシピエントの免疫細胞から攻撃を受けにくいT細胞を作製することに成功した。
本研究で示した方法は、国内外で開発の進む他家iPS細胞を用いたT細胞免疫療法において、近い将来に応用される可能性があります。

Report

(3 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • Research Products

    (7 results)

All 2021 2020 2019 Other

All Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (4 results) (of which Int'l Joint Research: 1 results) Remarks (2 results)

  • [Journal Article] Generation of hypoimmunogenic T cells from genetically engineered allogeneic human induced pluripotent stem cells2021

    • Author(s)
      Bo Wang, Shoichi Iriguchi, Masazumi Waseda, Norihiro Ueda, Tatsuki Ueda, Huaigeng Xu, Atsutaka Minagawa, Akihiro Ishikawa, Hisashi Yano, Tomoko Ishi, Ryoji Ito, Motohito Goto, Riichi Takahashi, Yasushi Uemura, Akitsu Hotta and Shin Kaneko
    • Journal Title

      Nature Biomedical Engineering

      Volume: in press Issue: 5 Pages: 429-440

    • DOI

      10.1038/s41551-021-00730-z

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Universal T cell generation for off-the-shelf cancer immunotherapy from gene edited allogeneic iPSCs2020

    • Author(s)
      Bo Wang, Shoichi Iriguchi, Masazumi Waseda, Norihiro Ueda, Tatsuki Ueda, Huaigeng Xu, Atsutaka Minagawa, Akihiro Ishikawa, Yasushi Uemura, Akitsu Hotta and Shin Kaneko
    • Organizer
      第19回日本再生医療学会総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Universal T cell generation for off-the-shelf cancer immunotherapy from gene edited allogeneic iPSCs2020

    • Author(s)
      Bo Wang (王 博)
    • Organizer
      第19回日本再生医療学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] Generation of "universal iPSC" with enhanced stealth ty on iPSC for allogeneic T cell immunotherapy2019

    • Author(s)
      Bo Wang (王 博)
    • Organizer
      第11回日本血液疾患免疫療法学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] Enhanced stealth property on iPSC to generate universal T cell source for allogeneic cancer immunotherapy2019

    • Author(s)
      Bo Wang (王 博)
    • Organizer
      17th International Congress of Immunology
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Remarks] 京都大学iPS細胞研究所

    • URL

      https://www.cira.kyoto-u.ac.jp/

    • Related Report
      2020 Annual Research Report
  • [Remarks] 金子研究室

    • URL

      http://www.cira.kyoto-u.ac.jp/kaneko/index.html

    • Related Report
      2020 Annual Research Report

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Published: 2019-09-03   Modified: 2022-01-27  

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