Characterization of novel acute myeloid leukemia-specific cell surface antigen identified as targets for CAR T cell therapy

• Project/Area Number: 20H03710
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Osaka University
• Principal Investigator: Hosen Naoki 大阪大学, 大学院医学系研究科, 教授 (10456923)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2022: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2021: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2020: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: CAR-T細胞 / ＣAR－Ｔ細胞 / CAR T細胞療法

Outline of Research at the Start

我々は急性骨髄性白血病に対するCAR T細胞の開発を目指したプロジェクト(AMED次世代がん研究)を開始した。すでに多数の新規急性骨髄性白血病特異的抗体を得ており、それらを元に作製したCAR T細胞の臨床応用へ向けて研究を進めている。そこで、本研究では、得られた新規急性骨髄性白血病特異的抗体が認識する抗原がどのようなものであるのかをを詳細に解析し、その白血病特異性のメカニズムを明らかにすることを目指した基礎的研究を行う。それにより、新たな切り口から急性骨髄性白血病の病態の理解を目指す。

Outline of Final Research Achievements

We identified 32 clones as antibodies that bind to AML cells but do not bind to peripheral blood of healthy individuals other than B cells, using expression cloning methods or LC-MS/MS analysis of immunoprecipitates. The antigens recognized by some candidate antibodies were identified by the random knockout method using CRISPR gRNA libraries. As a result, we identified 22 antigens out of 32 candidate antibodies. Among them, antigen A recognized by antibody X was expressed in normal blood cells and was not leukemia-specific, but antibody binding was leukemia-specific.Therefore, we narrowed down our research targets to them and created CAR-T cells derived from Antibody X, which showed an antitumor effect.

Academic Significance and Societal Importance of the Research Achievements

がん細胞特異的モノクロ―ナル抗体をできるだけ多く単離し、その後にそれらの抗体が認識する抗原の特性を丹念に解析することにより、網羅的なトランスクリプトーム解析では同的出来ないがん特異的細胞表面抗原を同定できるというコンセプトをAMLにおいても示すことができた。この結果は、新たなAMLに対するCAR-T細胞の臨床開発につながるだけでなく、他のがん種においても同様な試みがなされるべきであることを示唆している。

Research Products

• [Journal Article] Identification of glioblastoma-specific antigens expressed in patient-derived tumor cells as candidate targets for chimeric antigen receptor T cell therapy (2022)
  • Author(s): Nakagawa T, Kijima N, Hasegawa K, Ikeda S, Yaga M, Wibowo T, Tachi T, Kuroda H, Hirayama R, Okita Y, Kinoshita M, Kagawa N, Kanemura Y, Hosen N, Kishima H.
  • Journal Title: Neurooncol Adv. Volume: 5(1) Issue: 1
  • DOI: 10.1093/noajnl/vdac177
  • Peer Reviewed / Open Access
• [Journal Article] Signal-transducing adapter protein-1 is required for maintenance of leukemic stem cells in CML. (2020)
  • Author(s): Toda J, Ichii M, Oritani K, Shibayama H, Tanimura A, Saito H, Yokota T, Motooka D, Okuzaki D, Kitai Y, Muromoto R, Kashiwakura JI, Matsuda T, Hosen N, Kanakura Y.
  • Journal Title: Oncogene Volume: 39 Issue: 34 Pages: 5601-5615
  • DOI: 10.1038/s41388-020-01387-9
  • Peer Reviewed / Open Access
• [Presentation] Development of CAR-T cell therapy using xenograft models (2022)
  • Author(s): 保仙 直毅
  • Organizer: the 6th International Workshop on Humanized Mice
  • Int'l Joint Research / Invited
• [Presentation] 遺伝子改変T細胞療法. (2020)
  • Author(s): 保仙直毅.
  • Organizer: 第79回日本癌学会総会
  • Invited
• [Presentation] CAR-T cell therapy for multiple myeloma (2020)
  • Author(s): 保仙直毅.
  • Organizer: 第82回日本血液学会学術集会・総会
  • Invited