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.
Author Info: (1) Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA. (2) Department of Biomedical Engineering and Biological Design Center, Bo
Author Info: (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. (3) Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA. (4) Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA. (5) Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA. (6) Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, MA, USA. Electronic address: wilwong@bu.edu.
