Project Grant 2145853

CAREER: ENGINEERING NEXT-GENERATION CHIMERIC ANTIGEN RECEPTORS FOR CANCER IMMUNOTHERAPY USING PHOSPHO-PROTEOMICS -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.