Sense and Respond Gene Circuits to Enhance CAR-T Cell Safety and Efficacy
Current FDA-approved chimeric antigen receptor (CAR)-T cell therapies exhibit tremendous potential for treating cancer. However, challenges such as 1) the lack of tumor-specific antigens, 2) severe toxicity due to off-target effects, and 3) tumor-mediated immunosuppression limit the full potential of CAR-T cells. We aim to overcome these challenges by building logic-gated antigen receptors, safety switches, and immunostimulatory payload secreting CAR-T cells (Fig. 1). In addition, we also aim to develop an integrated system, an innovative gene circuit platform that combines logic-gate, safety switch, and controlled payload production in a single system, to enhance CAR-T cell safety and efficacy (Fig. 2). We aim to identify sensor that sense various tumor-microenvironment signatures and T-cell states, to reliably control CAR-T cell activation, differentiation, proliferation, and longevity.
If successful, we anticipate that this integrated system will be readily adopted by the CAR-T community to extend current existing CAR-T pipelines for treating various cancer types with enhanced specificity and efficacy, and further extend the success of CAR-T cells to treating additional solid tumors.