Li, Wong et al. developed a next-generation series of VIPER (versatile protease regulatable) CARs containing a viral protease domain (NS3 from hepatitis C) that could be controlled using safe, FDA-approved antiviral protease inhibitors such as grazoprevir. VIPER CARs engineered with inducible ON or OFF switches performed best-in-class in vitro compared to other drug-inducible CARs, were efficacious in xenograft leukemia models, prevented cytokine release syndrome (CRS) in a CRS mouse model, and could target multiple antigens. Additional multiplexed CAR T designs demonstrated advanced safety and efficacy.
Contributed by Katherine Turner
ABSTRACT: 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.