Universal Chimeric Antigen Receptors for Multiplexed and Logical Control of T Cell Responses

T cells expressing chimeric antigen receptors (CARs) are promising cancer therapeutic agents, with the prospect of becoming the ultimate smart cancer therapeutics. To expand the capability of CAR T cells, here, we present a split, universal, and programmable (SUPRA) CAR system that simultaneously encompasses multiple critical “upgrades,” such as the ability to switch targets without re-engineering the T cells, finely tune T cell activation strength, and sense and logically respond to multiple antigens. These features are useful to combat relapse, mitigate over-activation, and enhance specificity. We test our SUPRA system against two different tumor models to demonstrate its broad utility and humanize its components to minimize potential immunogenicity concerns. Furthermore, we extend the orthogonal SUPRA CAR system to regulate different T cell subsets independently, demonstrating a dually inducible CAR system. Together, these SUPRA CARs illustrate that multiple advanced logic and control features can be implemented into a single, integrated system. [Display omitted] •A split, universal, and programmable (SUPRA) CAR system for T cell therapy•SUPRA CAR can fine-tune T cell activation strength to mitigate toxicity•SUPRA CAR can sense and logically respond to multiple antigens to combat relapse•SUPRA CAR can inducibly control cell-type-specific signaling A chimeric antigen receptor system that can integrate signals from multiple antigens and fine-tune T cell activation in a cell-type-specific manner holds promise for enhancing the safety and specificity of CAR T cell therapies for cancer treatment.