Innovative Approaches to Enhance Chimeric Antigen Receptor (CAR) T-Cell Potency Using Quiescent T Cells

My research focuses on developing Chimeric Antigen Receptor (CAR) T cells for adoptive immunotherapy. The goal of the research is to enhance the efficacy of CAR T therapy by developing potent CAR T cells. Another goal of this research is to shorten the CAR T manufacturing period to increase the availability of this therapy in resource constraint health care settings, as well those patients with rapidly progressive disease. CAR T cells are generated by transducing activated T cells with lentiviral vectors and expanding their progeny over 9-14 days. T cells progressively differentiate over time. Transducing non-activated T cells with CAR will preserve the intrinsic stem-like properties of nave and memory T cells. This approach will yield CAR T cells with enhanced replicative capacity, engraftment, and in vivo activity. The purpose of this work is to determine the optimal T cell subset and corresponding optimal costimulatory domain for CAR when it is expressed in quiescent T cells. The scope of this research is that CAR T cells generated by transducing quiescent T cells will preserve the intrinsic stem-like properties of nave and memory T cells. We found that interplay of co-stimulation and metabolic engineering provides context-specific benefits which can be emphasized in distinct tumor environments. We also demonstrated that by blocking IFN1, we can increase the transduction efficiency and potency of nonactivated T cells.