High-performance multiplex drug-gated CAR circuits

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Chimeric antigen receptor (CAR) T cells can revolutionize cancer medicine, However, overactivation, lack of tumor-specific surface markers, and antigen escape have hampered CAR T cell development. A multi-antigen targeting CAR system regulated by clinically approved pharmaceutical agents is needed. Here, we present VIPER CARs (versatile protease regulatable CARs), a collection of inducible ON and OFF switch CAR circuits engineered with a viral protease domain. We established their controllability using FDA-approved antiviral protease inhibitors in a xenograft tumor and a cytokine release syndrome mouse model. Furthermore, we benchmarked VIPER CARs against other drug-gated systems and demonstrated best-in-class performance. We showed their orthogonality in vivo using the ON VIPER CAR and OFF lenalidomide-CAR systems. Finally, we engineered several VIPER CAR circuits by combining various CAR technologies. Our multiplexed, drug-gated CAR circuits represent the next progression in CAR design capable of advanced logic and regulation for enhancing the safety of CAR T cell therapy.
Publisher
CELL PRESS
Issue Date
2022-11
Language
English
Article Type
Article
Citation

CANCER CELL, v.40, no.11, pp.1294 - 1305

ISSN
1535-6108
DOI
10.1016/j.ccell.2022.08.008
URI
http://hdl.handle.net/10203/307069
Appears in Collection
BiS-Journal Papers(저널논문)
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