High-performance multiplex drug-gated CAR circuits
- Cancer Cell. 2022 Aug 26;S1535-6108(22)00372-5. doi: 10.1016/j.ccell.2022.08.008.
- 1. Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA.
- 2. Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
- 3. Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA. Electronic address: [email protected].
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.