Engineering clinically-approved drug gated CAR circuits

2020 
Chimeric antigen receptor (CAR) T cell immunotherapy has the potential to revolutionize cancer medicine. However, excessive CAR activation, lack of tumor-specific surface markers, and anti-gen escape have limited the safety and efficacy of CAR T cell therapy. A multi-antigen targeting CAR system that is regulated by safe, clinically-approved pharmaceutical agents is urgently needed, yet only a few simple systems have been developed, and even fewer have been evalu-ated for efficacy in vivo. Here, we present NASCAR (NS3 ASsociated CAR), a collection of in-ducible ON and OFF switch CAR circuits engineered with a NS3 protease domain deriving from the Hepatitis C Virus (HCV). We establish their ability to regulate CAR activity using multiple FDA-approved antiviral protease inhibitors, including grazoprevir (GZV), both in vitro and in a xenograft tumor model. In addition, we have engineered several dual-gated NASCAR circuits, consisting of an AND logic gate CAR, universal ON-OFF CAR, and a switchboard CAR. These engineered receptors enhance control over T cell activity and tumor-targeting specificity. To-gether, our comprehensive set of multiplex drug-gated CAR circuits represent a dynamic, tuna-ble, and clinically-ready set of modules for enhancing the safety of CAR T cell therapy.
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