CAREER: Engineering next-generation chimeric antigen receptors for cancer immunotherapy using phospho-proteomics

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The immune system fights cancer as well as infections. Cancer immunotherapy attempts to harness and bolster this capability. One FDA-approved immunotherapy involves modifying white blood cells from the patient to recognize and attack tumor cells. The resulting cells are referred to as CAR-T cells. Understanding CAR-T activity could enable design of improved cancer immunotherapy. Identifying the signaling pathways that enhance tumor killing in CAR-T cells is a primary objective of the project. This research project will integrate a broader educational plan to educate students, teachers, and the public. Multi-year outreach to a local high school will provide hands-on experience to a predominantly Hispanic student population. Chimeric antigen receptors (CARs) are comprised of modular protein domains including intracellular signaling/co-stimulation domains. CAR activation stimulates intracellular phosphorylation cascades that promote the cytotoxic functions of T cells. Phospho-proteomics offers quantitative characterization of protein phosphorylation. The governing hypothesis is that a rigorous and comprehensive investigation of CAR signaling using phospho-proteomics will uncover principles of CAR function. This could enable rational engineering of next-generation CARs. Using CD19 as a model antigen, this project will attempt to expand knowledge of CAR signaling and CAR design criteria. The project will pursue the following scientific objectives: 1) Identify signaling pathways that promote CAR-T cell cytotoxic function; 2) Define CAR signaling pathways that enable resistance to exhaustion; and 3) Develop third-generation CARs with improved cytotoxicity and increased persistence. This research will establish a platform that can be used for engineering analysis of CAR signaling and will provide a general framework for CAR design.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.