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Targeting FLT3-specific chimeric antigen receptor T cells for acute lymphoblastic leukemia with KMT2A rearrangement

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Abstract

CD19-specific chimeric antigen receptor T (CAR T) immunotherapy is used to treat B-cell malignancies. However, antigen-escape mediated relapse following CAR T therapy has emerged as a major concern. In some relapsed cases, especially KMT2A rearrangement-positive B-acute lymphoblastic leukemia (KMT2A-r B-ALL), most of the B-cell antigens are lost via lineage conversion to the myeloid phenotype, rendering multi-B-cell-antigen-targeted CAR T cell therapy ineffective. Fms-related tyrosine kinase-3 (FLT3) is highly expressed in KMT2A-r B-ALL; therefore, in this study, we aimed to evaluate the antitumor efficacy of CAR T cells targeting both CD19 and FLT3 in KMT2A-r B-ALL cells. We developed piggyBac transposon-mediated CAR T cells targeting CD19, FLT3, or both (dual) and generated CD19-negative KMT2A-r B-ALL models through CRISPR-induced CD19 gene-knockout (KO). FLT3 CAR T cells showed antitumor efficacy against CD19-KO KMT2A-r B-ALL cells both in vitro and in vivo; dual-targeted CAR T cells showed cytotoxicity against wild-type (WT) and CD19-KO KMT2A-r B-ALL cells, whereas CD19 CAR T cells demonstrated cytotoxicity only against WT KMT2A-r B-ALL cells in vitro. Therefore, targeting FLT3-specific CAR T cells would be a promising strategy for KMT2A-r B-ALL cells even with CD19-negative relapsed cases.

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Acknowledgements

The authors acknowledge Ms. Kumiko Yamashima and Ms. Mami Kotoura for their valuable technical assistance and Ms. Mika Tanimura, Ms. Ryoko Murata, and Ms. Yasuko Hashimoto for their secretarial assistance. The authors also thank Editage (http://www.editage.com) for proofreading, editing, and reviewing this manuscript. This work was supported by the Japan Agency for Medical Research and Development (AMED) (18ck0106413h0001), JSPS KAKENHI (19K08326) and Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics.

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Authors and Affiliations

  1. Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan

    Masaya Suematsu, Shigeki Yagyu, Hideki Yoshida, Shinya Osone, Toshihiko Imamura & Tomoko Iehara

  2. Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Japan

    Yozo Nakazawa

  3. Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan

    Kanji Sugita

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Conceptualization, SY, YN, SO, TI, and TI; Methodology, MS, SY, HY, and YN; Investigation, MS, SY; Writing—Original Draft, MS, and SY; Writing—Review & Editing, MS, SY, SO, HY, TI, YN, TI, and TI; Funding Acquisition, SY and SO; Resources, SY, TI, and TI; Supervision, SY, TI, and TI.

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Suematsu, M., Yagyu, S., Yoshida, H. et al. Targeting FLT3-specific chimeric antigen receptor T cells for acute lymphoblastic leukemia with KMT2A rearrangement. Cancer Immunol Immunother 72, 957–968 (2023). https://doi.org/10.1007/s00262-022-03303-4

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