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 sensors that sense various tumor-microenvironment signatures and T-cell states to reliably control CAR-T cell activation, differentiation, proliferation, and longevity.

This integrated system will enhance the specificity and efficacy of existing CAR-T pipelines for various cancer types, and further extend the success of CAR-T cells to treat solid tumors.

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