Improved safety of chimeric antigen receptor T cells indirectly targeting antigens via switchable adapters

Hyung Bae Park, Ki Hyun Kim, Ju Hwan Kim, Sang Il Kim, Yu Mi Oh, Miseung Kang, Seoho Lee, Siwon Hwang, Hyeonmin Lee, TaeJin Lee, Seungbin Park, Ji Eun Lee, Ga Ram Jeong, Dong Hyun Lee, Hyewon Youn, Eun Young Choi, Woo Chan Son, Sang J. Chung (), Junho Chung () and Kyungho Choi ()
Additional contact information
Hyung Bae Park: Seoul National University College of Medicine
Ki Hyun Kim: Seoul National University College of Medicine
Ju Hwan Kim: AbTis Co. Ltd.
Sang Il Kim: Seoul National University College of Medicine
Yu Mi Oh: Seoul National University College of Medicine
Miseung Kang: Seoul National University College of Medicine
Seoho Lee: Seoul National University College of Medicine
Siwon Hwang: Seoul National University College of Medicine
Hyeonmin Lee: Seoul National University College of Medicine
TaeJin Lee: AbTis Co. Ltd.
Seungbin Park: Sungkyunkwan University
Ji Eun Lee: Seoul National University College of Medicine
Ga Ram Jeong: Seoul National University College of Medicine
Dong Hyun Lee: University of Ulsan College of Medicine, Asan Medical Center
Hyewon Youn: Seoul National University College of Medicine
Eun Young Choi: Seoul National University College of Medicine
Woo Chan Son: University of Ulsan College of Medicine, Asan Medical Center
Sang J. Chung: Sungkyunkwan University
Junho Chung: Seoul National University College of Medicine
Kyungho Choi: Seoul National University College of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Chimeric antigen receptor T (CAR-T) cells show remarkable efficacy for some hematological malignancies. However, CAR targets that are expressed at high level and selective to tumors are scarce. Several strategies have been proposed to tackle the on-target off-tumor toxicity of CAR-T cells that arise from suboptimal selectivity, but these are complicated, with many involving dual gene expression for specificity. In this study, we show that switchable CAR-T cells with a tumor targeting adaptor can mitigate on-target off-tumor toxicity against a low selectivity tumor antigen that cannot be targeted by conventional CAR-T cells, such as CD40. Our system is composed of anti-cotinine murine CAR-T cells and cotinine-labeled anti-CD40 single chain variable fragments (scFv), with which we show selective tumor killing while sparing CD40-expressing normal cells including macrophages in a mouse model of lymphoma. Simple replacement of the tumor-targeting adaptor with a suicidal drug-conjugated tag may further enhance safety by enabling permanent in vivo depletion of the switchable CAR-T cells when necessary. In summary, our switchable CAR system can control CAR-T cell toxicity while maintaining therapeutic efficacy, thereby expanding the range of CAR targets.

Date: 2024
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DOI: 10.1038/s41467-024-53996-7

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