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Development of CAR-T cells to treat recurring leukemia post-HCT by targeting mismatched HLA-DP

Research Project

Project/Area Number 21K08369
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionNagoya University

Principal Investigator

AKATSUKA YOSHIKI  名古屋大学, 医学系研究科, 特任教授 (70333391)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2023: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords移植片対白血病効果 / キメラ抗原受容体T細胞 / HLA-DP / アロ抗原 / キメラ抗原受容体 / HLA / 同種抗体 / CAR-T細胞 / 遺伝子改変T細胞 / 同種造血幹細胞移植
Outline of Research at the Start

難治性造血器腫瘍に対する同種造血細胞移植は根治療法として確立されてきたが、再発が成績向上の足かせとなっている。移植片対腫瘍(GVT)効果の標的として白血病抗原、マイナー抗原および不適合HLA抗原があるが、このうちHLA-DP不適合はGVHDを増やすものの、GVT効果もあること、さらに非血縁者間移植の70%でDP不適合が認められるため、これを標的とする治療法の開発を計画した。申請者はDP不適合移植後患者より樹立した細胞傷害性T細胞から取得したT細胞受容体遺伝子改変T細胞を開発しており、さらに抗体をHLA-DP抗原受容体とした新たな細胞治療製剤としてCAR-T細胞を開発することを目標とする。

Outline of Final Research Achievements

In HLA-8/8-matched unrelated allogeneic transplantation for hematological malignancies, HLA-DP is often mismatched at a rate of 70%, which can be applied to treat or prevent post-transplant relapsed malignancy by graft-versus-tumor effect. We have established a technique to flow-sort hybridoma cells which produce antibodies of interest by introducing CD64 Fc receptor into the hybridoma cells in advance and allow the produced antibodies to bind to the self CD64. With this method, two hybridomas producing antibodies specific for HLA-DPB1*09:01 (common in Japanese) were isolated so far. In parallel, by using RT-PCR we cloned genes encoding IgG antibodies specific for several HLA subtypes and generated single-chain antibodies that retain the original antibodies’ specificity. Thus, we currently working on generation of chimeric antigen receptor-gene modified T cells specific for HLA-DP of interest.

Academic Significance and Societal Importance of the Research Achievements

同種造血細胞移植におけるドナー/患者間のHLA-DP不適合はGVT効果発現に重要である。不適合HLA-DPを認識するT細胞の樹立は容易ではなく、事前にHLA-DPを認識する抗体を樹立し、その遺伝子配列を元にキメラ抗原受容体T細胞調製に必要なベクターを作製しておけば直ちに養子免疫療法を実施することが可能となる。この抗HLA-DP抗体は殆ど報告がなく、我々はフローサイトメトリーを使った方法で狙った抗原に特異的な抗体を作るハイブリドーマ細胞を樹立する方法を確立した。この2つの技術を組み合わせることで将来的にさまざまなHLA-DP型不適合に対応するキメラ抗原受容体T細胞を提供できると考えられる。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (12 results)

All 2023 2022 2021

All Journal Article (6 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 3 results,  Open Access: 2 results) Presentation (6 results)

  • [Journal Article] Development of TCR-T cell therapy targeting mismatched HLA-DPB1 for relapsed leukemia after allogeneic transplantation.2023

    • Author(s)
      Barakat C, Inagaki Y, Mizuno S, Nishio N, Katsuyama N, Sato Y, Kobayashi M, Ozeki K, Iida H, Tomita A, Sawa M, Demachi-Okamura A, Takahashi Y, Nishikawa H, Akatsuka Y.
    • Journal Title

      Int J Hematol

      Volume: 118 Issue: 2 Pages: 252-266

    • DOI

      10.1007/s12185-023-03621-y

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] T cell receptor-engineered T cells derived from target human leukocyte antigen-DPB1-specific T cell can be a potential tool for therapy against leukemia relapse following allogeneic hematopoietic cell transplantation2023

    • Author(s)
      Katsuyama N, Kawase T, Barakat C, Mizuno S, Tomita A, Ozeki K, Nishio N, Sato Y, Kajiya R, Shiraishi K, Takahashi Y, Ichinohe T, Nishikawa H, Akatsuka Y
    • Journal Title

      Nagoya Journal of Medical Science

      Volume: 85 Issue: 4 Pages: 779-796

    • DOI

      10.18999/nagjms.85.4.779

    • ISSN
      0027-7622
    • URL

      https://nagoya.repo.nii.ac.jp/records/2008446

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Hematological immune-related adverse events of immune checkpoint inhibitors and their management2023

    • Author(s)
      Akatsuka Y
    • Journal Title

      Rinsho Ketsueki

      Volume: 64 Issue: 8 Pages: 782-790

    • DOI

      10.11406/rinketsu.64.782

    • ISSN
      0485-1439, 1882-0824
    • Related Report
      2023 Annual Research Report
  • [Journal Article] T cell receptor-engineered T cells derived from target human leukocyte antigen-DPB1-specific T cell can be a potential tool for therapy against leukemia relapse following allogeneic hematopoietic cell transplantation2023

    • Author(s)
      Katsuyama N, Kawase T, Barakat C, Mizuno S, Tomita A, Ozeki K, Nishio N, Sato Y, Kajiya R, Shiraishi K, akahashi Y, Ichinohe T, Nishikawa H, Akatsuka Y
    • Journal Title

      Nagoya J Med Sci

      Volume: -

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] 不適合アロ抗原を認識するT細胞受容体を用いた移植後再発白血病に対する遺伝子改変T細胞の開発2022

    • Author(s)
      赤塚美樹
    • Journal Title

      BIO Clinica

      Volume: 37(6) Pages: 75-81

    • Related Report
      2022 Research-status Report
  • [Journal Article] 不適合アロ抗原認識抗体を用いた移植後再発白血病に対するCAR-T細胞の開発2021

    • Author(s)
      赤塚美樹
    • Journal Title

      Bio Clinica

      Volume: 36 Pages: 56-63

    • Related Report
      2021 Research-status Report
  • [Presentation] 同種造血幹細胞移植後の白血病再発に対するTCR-T細胞療法の開発.2023

    • Author(s)
      1.Carolyne BARAKAT, Yuichiro INAGAKI, Shohei MIZUNO, Naoya KATSUYAMA, Yoshie SATO, Miki KOBAYASHI, Kazutaka OZEKI, Akihiro TOMITA, Hiroatsu Iida, Masashi SAWA, Yoshiki AKATSUKA.
    • Organizer
      第15回日本血液疾患免疫療法学会
    • Related Report
      2023 Annual Research Report
  • [Presentation] トランスポゾンを用いたTCR-T細胞調整条件の検討2023

    • Author(s)
      2.陳 浩, 木村実茂, Carolyne Barakat, 西尾信博, 佐藤由英, 鈴木哲, 岡村文子, 高橋義行, 赤塚美樹.
    • Organizer
      第27回日本がん免疫学会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Development of TCR-T cell Adoptive immunotherapy targeting mismatched HLA-DPB1 for leukemia relapse after allogeneic hematopoietic stem cell transplantation.2023

    • Author(s)
      3.Carolyne BARAKAT, Naoya KATSUYAMA, Yoshie SATO, Miki KOBAYASHI, Yuichiro INAGAKI, Kazutaka OZEKI, Shohei MIZUNO, Akihiro TOMITA, Masashi SAWA, Yoshiki AKATSUKA.
    • Organizer
      2nd JCA-AACR Precision Cancer Medicine International Conference.
    • Related Report
      2023 Annual Research Report
  • [Presentation] 不適合HLA-DPを同種標的とした白血病に対するTCR-T細胞療法の開発2023

    • Author(s)
      Carolyne Barakat, 勝山 直哉, 佐藤 由英, 小林 美希, 稲垣 裕一郎, 水野 昌平, 尾関 和貴, 冨田 章裕, 澤 正史, 赤塚 美樹
    • Organizer
      第45回日本造血・免疫細胞療法学会
    • Related Report
      2022 Research-status Report
  • [Presentation] Establishment of T cell clones specific for mismatched HLA-DP molecules toward development of adoptive cell therapy for leukemia following allogeneic hematopoietic cell transplantation.2022

    • Author(s)
      Carolyne Baraka, 勝山 直, 佐藤 由, 小林 美, 稲垣 裕, 尾関 和, 水野 昌, 冨田 章, 赤塚 美樹
    • Organizer
      第5回 東海北陸HLA研究会
    • Related Report
      2022 Research-status Report
  • [Presentation] 非血縁者間移植患者からの不適合HLA-DP特異的クローンの樹立2022

    • Author(s)
      赤塚 美樹, 勝山 直哉, 稲垣 裕一郎, 水野 昌平, 尾関 和貴, 冨田 章裕, 澤 正史
    • Organizer
      第84回日本血液学会総会
    • Related Report
      2022 Research-status Report

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Published: 2021-04-28   Modified: 2025-01-30  

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