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Development of CAR-T cell therapy for KMT2A-rearranged acute lymphoblastic leukemia

Research Project

Project/Area Number 19K08326
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52050:Embryonic medicine and pediatrics-related
Research InstitutionKyoto Prefectural University of Medicine

Principal Investigator

Osone Shinya  京都府立医科大学, 医学(系)研究科(研究院), 講師 (60708717)

Co-Investigator(Kenkyū-buntansha) 細井 創  京都府立医科大学, 医学(系)研究科(研究院), 特任教授 (20238744)
家原 知子  京都府立医科大学, 医学(系)研究科(研究院), 教授 (20285266)
今村 俊彦  京都府立医科大学, 医学(系)研究科(研究院), 講師 (30444996)
柳生 茂希  京都府立医科大学, 医学(系)研究科(研究院), 助教 (10572547)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
KeywordsCAR-T細胞療法 / KMT2A再構成 / 急性リンパ性白血病 / ピギーバックトランスポゾンベクター / CD19 / FLT3 / CAR-T細胞 / CAR-T療法
Outline of Research at the Start

乳児期発症の、KMT2A(MLL)遺伝子再構成を伴う急性リンパ性白血病(ALL)の予後は、いまだ不良である。近年、難治性白血病に対する新たな治療としてCAR-T細胞療法が注目されている。そこで我々は、KMT2遺伝子再構成を伴うALLに対する、新規のCAR-T細胞を作成して、その効果を培養ALL細胞やマウスモデルを用いて検討し、この予後不良なALLに対する新たな治療法の開発を目指す。

Outline of Final Research Achievements

KMT2A-rearranged acute lymphoblastic leukemia (KMT2A-R ALL) occurs in infancy and has resulted in dismal outcome. We tried to develop dual CAR-T cell therapy targeting both CD19 and FLT3. We generated dual CAR-T cells recognizing both CD19 and FLT3, by using non-viral Piggy-Bac transposon vectors. The dual CAR-T cells showed antigen-specific cytotoxicity against KMT2A-R ALL cells. This dual CAR-T cell therapy might be a promising therapy for KMT2A-R ALL.

Academic Significance and Societal Importance of the Research Achievements

本研究では、現在でも予後不良であるKMT2A再構成をもつ急性リンパ性白血病(KMT2A-R ALL)に対する新たな治療として、CD19とFLT3をどちらも認識できる新たなCAR-T細胞(dual CAR-T)を作製した。私たちが作成したdual CAR-T細胞を、KMT2A-R ALL細胞と共に培養したところ、dual CAR-T細胞はALL細胞を殺傷することができた。Dual CAR-T細胞治療は、KMT2A-R ALLに対する新規治療として有望である。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (34 results)

All 2022 2021 2020 2019 Other

All Int'l Joint Research (2 results) Journal Article (14 results) (of which Peer Reviewed: 13 results,  Open Access: 10 results) Presentation (18 results) (of which Int'l Joint Research: 5 results,  Invited: 1 results)

  • [Int'l Joint Research] National Cancer Center Singapore(シンガポール)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] Chulalongkorn大学(タイ)

    • Related Report
      2021 Annual Research Report
  • [Journal Article] PiggyBac Transposon-Mediated CD19 Chimeric Antigen Receptor-T Cells Derived From CD45RA-Positive Peripheral Blood Mononuclear Cells Possess Potent and Sustained Antileukemic Function2022

    • Author(s)
      Suematsu Masaya、Yagyu Shigeki、Nagao Nobuyoshi、Kubota Susumu、Shimizu Yuto、Tanaka Miyuki、Nakazawa Yozo、Imamura Toshihiko
    • Journal Title

      Frontiers in Immunology

      Volume: 13 Pages: 1-13

    • DOI

      10.3389/fimmu.2022.770132

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibition of MEK pathway enhances the antitumor efficacy of chimeric antigen receptor T cells against neuroblastoma2021

    • Author(s)
      Tomida Akimasa、Yagyu Shigeki、Nakamura Kayoko、Kubo Hiroshi、Yamashima Kumiko、Nakazawa Yozo、Hosoi Hajime、Iehara Tomoko
    • Journal Title

      Cancer Science

      Volume: 112 Issue: 10 Pages: 4026-4036

    • DOI

      10.1111/cas.15074

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A lymphodepleted non‐human primate model for the assessment of acute on‐target and off‐tumor toxicity of human chimeric antigen receptor‐T cells2021

    • Author(s)
      Yagyu Shigeki、Mochizuki Hidemi、Yamashima Kumiko、Kubo Hiroshi、Saito Shoji、Tanaka Miyuki、Sakamoto Kengo、Shimoi Akihito、Nakazawa Yozo
    • Journal Title

      Clinical Translational Immunology

      Volume: 10 Issue: 6 Pages: 1291-1291

    • DOI

      10.1002/cti2.1291

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mutated GM-CSF-based CAR-T cells targeting CD116/CD131 complexes exhibit enhanced anti-tumor effects against acute myeloid leukaemia2021

    • Author(s)
      Hasegawa Aiko、Saito Shoji、Narimatsu Shogo、Nakano Shigeru、Nagai Mika、Ohnota Hideki、Inada Yoichi、Morokawa Hirokazu、Nakashima Ikumi、Morita Daisuke、Ide Yuichiro、Matsuda Kazuyuki、Tashiro Haruko、Yagyu Shigeki、Tanaka Miyuki、Nakazawa Yozo
    • Journal Title

      Clinical Translational Immunology

      Volume: 10 Issue: 5 Pages: 1282-1282

    • DOI

      10.1002/cti2.1282

    • URL

      https://localhost/en/publications/d62b93f1-a412-47d8-969f-7a2c74eadcd4

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Autologous antigen-presenting cells efficiently expand piggyBac transposon chimeric antigen receptor T cells with predominant memory phenotype.2021

    • Author(s)
      Nakamura K, Yagyu S, Hirota S, Tomida A, Kondo M, Shigeura T, Hasegawa A, Tanaka M, Nakazawa Y.
    • Journal Title

      Molecular Therapy - Methods and Clinical Development

      Volume: 21 Pages: 315-324

    • DOI

      10.1016/j.omtm.2021.03.011

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of non-viral, ligand-dependent, EPHB4-specific chimeric antigen receptor T cells for treatment of rhabdomyosarcoma.2021

    • Author(s)
      Kubo H, Yagyu S, Nakamura K, Yamashima K, Tomida A, Kikuchi K, Iehara T, Nakazawa Y, Hosoi H.
    • Journal Title

      Molecular Therapy - Oncolytics

      Volume: 20 Pages: 646-658

    • DOI

      10.1016/j.omto.2021.03.001

    • Related Report
      2021 Annual Research Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] ピギーバックトランスポゾンを用いた遺伝子改変キメラ抗原受容体T細胞の開発2021

    • Author(s)
      柳生茂希,中沢洋三
    • Journal Title

      臨床免疫・アレルギー科

      Volume: 75 Pages: 515-520

    • Related Report
      2021 Annual Research Report
  • [Journal Article] Lymphodepleted non-human primate model for the assessment of acute on-target and off-tumor toxicity of human CAR-T cells.2021

    • Author(s)
      Yagyu S, Mochizuki H, Yamashima K, Kubo H, Saito S, Tanaka M, Sakamoto K, Shimoi A, Nakazawa Y.
    • Journal Title

      Clinical & Translational Immunology

      Volume: -

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mutated GM-CSF-based CAR T-cells targeting CD116/CD131 complexes exhibit enhanced anti-tumor effects against AML.2021

    • Author(s)
      Hasegawa A, Saito A, Narimatsu S, Nakano S, Nagai M, Ohnota H, Inada Y, Morokawa H, Nakashima I, Morita D, Ide Y, Matsuda K, Tashiro H, Yagyu S, Tanaka M, Nakazawa Y.
    • Journal Title

      Clinical & Translational Immunology

      Volume: -

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Autologous non-human primate model for safety assessment of piggyBac transposon-mediated chimeric antigen receptor T cells on granulocyte-macrophage colony-stimulating factor receptor.2020

    • Author(s)
      Morokawa H, Yagyu S, Hasegawa A, Tanaka M, Saito S, Mochizuki H, Sakamoto K, Shimoi A, Nakazawa Y.
    • Journal Title

      Clinical & Translational Immunology

      Volume: 22 Issue: 11

    • DOI

      10.1002/cti2.1207

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Supportive care for hemostatic complications associated with pediatric leukemia: a national survey in Japan2019

    • Author(s)
      Shinya Osone, Keitaro Fukushima, Michihiro Yano, Mariko Kakazu, Hirozumi Sano, Yoko Kato, Yuichi Shinkoda, Kunihiro Shinoda, Naoko Mori, Souichi Adachi
    • Journal Title

      International Journal of Hematology

      Volume: 110 Issue: 6 Pages: 743-750

    • DOI

      10.1007/s12185-019-02740-9

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Disordered hemostasis associated with severely depressed fibrinolysis demonstrated using a simultaneous thrombin and plasmin generation assay during L‐asparaginase induction therapy in pediatric acute lymphoblastic leukemia2019

    • Author(s)
      Ishihara Takashi、Nogami Keiji、Ochi Satoshi、Ishida Toshiaki、Kosaka Yoshiyuki、Sawada Akihisa、Inoue Masami、Osone Shinya、Imamura Toshihiko、Hosoi Hajime、Shima Midori
    • Journal Title

      Pediatric Blood & Cancer

      Volume: 67 Issue: 1

    • DOI

      10.1002/pbc.28016

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Successful treatment with 2-chlorodeoxyadenosine of refractory pediatric Langerhans cell histiocytosis with initial involvement of the gastrointestinal tract2019

    • Author(s)
      Azusa Mayumi, Toshihiko Imamura, Kenichi Sakamoto, Takeshi Ota, Shinya Osone, Ikuya Usami, Hajime Hosoi
    • Journal Title

      International Journal of Hematology

      Volume: 110 Issue: 6 Pages: 756-762

    • DOI

      10.1007/s12185-019-02711-0

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cellular and molecular characteristics of established neuroblastoma cell lines.2019

    • Author(s)
      Tohru Sugimoto, Hiroshi Kuroda, Sigeki Yagyu, Takahiro Gotoh, Shinya Osone, Shinchi Tamura, Tomoko Iehara, Hajime Hosoi
    • Journal Title

      Journal of Cancer Research and Therapeutic Oncology

      Volume: 7 Pages: 1-15

    • DOI

      10.17303/jcrto.2019.7.201

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Recent advances of CAR-T cell therapy for pediatric solid tumors.2021

    • Author(s)
      Yagyu S, et al.
    • Organizer
      Annual Meeting of Japanese Society of Pediatrics
    • Related Report
      2021 Annual Research Report
  • [Presentation] piggyBac transposon-mediated CAR-T cells for solid tumors - A promising approach for clinical application.2021

    • Author(s)
      Yagyu S, et al.
    • Organizer
      The 12th JSH International Symposium 2021 in Kamakura.
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 悪性固形腫瘍に対する非ウイルス遺伝子改変キメラ抗原受容体T細胞の開発2021

    • Author(s)
      柳生茂希
    • Organizer
      AMED再生・細胞医療・遺伝子治療研究開発交流会シンポジウム
    • Related Report
      2021 Annual Research Report
  • [Presentation] Non-viral gene transfer based chimeric antigen receptor T cells for solid tumors2021

    • Author(s)
      柳生茂希
    • Organizer
      第27回日本遺伝子細胞治療学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Non-viral gene transfer based chimeric antigen receptor T cells for solid tumors - 悪性固形腫瘍に対するCAR-T細胞の開発 -2021

    • Author(s)
      Yagyu S, et al.
    • Organizer
      第27回日本遺伝子細胞治療学会学術集会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Development of multi-antigen specific chimeric antigen receptor T cells for acute lymphoblastic leukemia with rearrangement of KMT2A gene.2021

    • Author(s)
      Suematsu M, Yagyu S, Osone S, et al.
    • Organizer
      第63回日本小児血液・がん学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] PiggyBac transposon mediated CD19 CAR-T cells derived from CD45RA-positive PBMCs possess potent and sustained antileukemic function.2021

    • Author(s)
      Suematsu M, Yagyu S, et al.
    • Organizer
      64th Annual meeting of American Society of Hematology.
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Lymphodepleted non-human primate model for the assessment of acute on-target and off-tumor toxicity of human CAR-T cells.2021

    • Author(s)
      Yagyu S, et al.
    • Organizer
      49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology, ASI 2021.
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 固形腫瘍を標的とした非ウイルス遺伝子改変CAR-T細胞の開発2020

    • Author(s)
      柳生茂希
    • Organizer
      第4回WAKO Web受託セミナー
    • Related Report
      2020 Research-status Report
  • [Presentation] リアルタイム細胞アナライザーを用いた遺伝子改変キメラ抗原受容体T細胞の機能解析2020

    • Author(s)
      柳生茂希
    • Organizer
      Agilentオンライン細胞解析セミナー2020
    • Related Report
      2020 Research-status Report
  • [Presentation] piggyBac transposon-mediated CAR-T cells - A promising and realistic approach for clinical application.2020

    • Author(s)
      Yagyu S
    • Organizer
      International Society of Cell Therapy 2020
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] piggyBac transposon mediated CAR-T cells for solid tumor - A promising and realistic approach for clinical application.2020

    • Author(s)
      Yagyu S
    • Organizer
      第79回日本癌学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] Combination therapy of GD2-specific CAR-T cell with Tyrosine Kinase inhibitor for neuroblastoma cells.2020

    • Author(s)
      Tomida A, Yagyu S, Yamashima K, Kubo H, Iehara T, Nakazawa Y, Hosoi H.
    • Organizer
      23rd Annual Meeting of American Society of Gene and Cell Therapy.
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] 再発B前駆細胞型急性リンパ性白血病のクローン進化の検討2019

    • Author(s)
      眞弓あずさ,今村俊彦,飯島友加,冨井敏宏,西島 大,友安千紘,矢野未央,田村真一,大曽根眞也,石田宏之,白石友一,黒田啓史,宮野 悟,堀部敬三,小川誠治,眞田 昌,細井 創
    • Organizer
      第122回日本小児科学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 小児がん拠点病院である当院における終末期在宅医療の現状2019

    • Author(s)
      宮地 充,柳生茂希,大曽根眞也,土屋邦彦,今村俊彦,家原知子,細井 創
    • Organizer
      第57回日本癌治療学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] FANCI遺伝子変異が同定された乳児期発症ファンコニ―貧血の1例2019

    • Author(s)
      浦田貴代,今村俊彦,大曽根眞也,村松秀城,高橋義行,細井 創
    • Organizer
      第61回日本小児血液・がん学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 類白血病反応を伴った1型高IgE症候群の乳児例2019

    • Author(s)
      野田佳奈子,今村俊彦,大曽根眞也,岡本圭祐,井澤和司,金兼弘和,牧野 茂,今宿晋作,細井 創
    • Organizer
      第61回日本小児血液・がん学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] BRCA1とMLH1の胚細胞変異を有する急性巨核芽球性白血病(AMKL)の1例2019

    • Author(s)
      末松正也,今村俊彦,大曽根眞也,堂 淳子,吉田仁典,加藤元博,細井 創
    • Organizer
      第61回日本小児血液・がん学会学術集会
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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