This Project Grant award from the National Cancer Institute (CFDA 93.395 Cancer Treatment Research) provides $642,044 to the University of Washington to engineer a synthetic feedback control system for regulating T cell signaling to improve the efficacy of T cell-based cancer immunotherapies. The goal is to develop a system that can maintain optimal T cell signaling to sustain anti-tumor effector functions while mitigating T cell exhaustion, a common challenge with current engineered T cell therapies, particularly against solid tumors. The project involves quantifying the input-output relationships of T cell signaling pathways, identifying genetic components for feedback control, and testing prototype feedback circuits in a mouse tumor model. The University of Washington has subcontracted a portion of this work to the Fred Hutchinson Cancer Center. If successful, this project could establish a new paradigm for engineering self-regulating cell therapies with enhanced and sustained anti-tumor activity.