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Cyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cells

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  • Yixi Zhang

    (Zhejiang University School of Medicine
    Chinese Academy of Medical Sciences)

  • Hongyu Fang

    (Zhejiang University School of Medicine
    Chinese Academy of Medical Sciences)

  • Guocan Wang

    (Zhejiang University School of Medicine
    Chinese Academy of Medical Sciences)

  • Guangxun Yuan

    (Zhejiang University School of Medicine
    Chinese Academy of Medical Sciences)

  • Ruoyu Dong

    (Zhejiang University School of Medicine)

  • Jijun Luo

    (Zhejiang University School of Medicine
    Chinese Academy of Medical Sciences)

  • Yu Lyu

    (Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, International Campus, Zhejiang University)

  • Yajie Wang

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center)

  • Peng Li

    (Puluoting Health Technology Co., Ltd)

  • Chun Zhou

    (Zhejiang University School of Medicine)

  • Weiwei Yin

    (Zhejiang University
    Zhejiang University School of Medicine)

  • Haowen Xiao

    (Zhejiang University School of Medicine)

  • Jie Sun

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center)

  • Xun Zeng

    (Zhejiang University School of Medicine
    Chinese Academy of Medical Sciences)

Abstract

Chimeric antigen receptor (CAR)-T therapy requires autologous T lymphocytes from cancer patients, a process that is both costly and complex. Universal CAR-T cell treatment from allogeneic sources can overcome this limitation but is impeded by graft-versus-host disease (GvHD) and host versus-graft rejection (HvGR). Here, we introduce a mutated calcineurin subunit A (CNA) and a CD19-specific CAR into the T cell receptor α constant (TRAC) locus to generate cells that are resistant to the widely used immunosuppressant, cyclosporine A (CsA). These immunosuppressant-resistant universal (IRU) CAR-T cells display improved effector function in vitro and anti-tumour efficacy in a leukemia xenograft mouse model in the presence of CsA, compared with CAR-T cells carrying wild-type CNA. Moreover, IRU CAR-T cells retain effector function in vitro and in vivo in the presence of both allogeneic T cells and CsA. Lastly, CsA withdrawal restores HvGR, acting as a safety switch that can eliminate IRU CAR-T cells. These findings demonstrate the efficacy of CsA-resistant CAR-T cells as a universal, ‘off-the-shelf’ treatment option.

Suggested Citation

  • Yixi Zhang & Hongyu Fang & Guocan Wang & Guangxun Yuan & Ruoyu Dong & Jijun Luo & Yu Lyu & Yajie Wang & Peng Li & Chun Zhou & Weiwei Yin & Haowen Xiao & Jie Sun & Xun Zeng, 2023. "Cyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cells," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44176-0
    DOI: 10.1038/s41467-023-44176-0
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    1. Stefan Klein-Hessling & Khalid Muhammad & Matthias Klein & Tobias Pusch & Ronald Rudolf & Jessica Flöter & Musga Qureischi & Andreas Beilhack & Martin Vaeth & Carsten Kummerow & Christian Backes & Rou, 2017. "NFATc1 controls the cytotoxicity of CD8+ T cells," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
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