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LEARNING FEATURES OF OPTIMAL CAR T CELLS FOR LBCL FROM PATIENT DATA - PROJECT SUMMARY/ABSTRACT CHIMERIC ANTIGEN RECEPTOR (CAR) T CELLS HAVE EMERGED AS BREAKTHROUGH TREATMENTS FOR PATIENTS WITH HEMATOLOGIC MALIGNANCIES, EARNING 12 APPROVALS FROM THE U.S. FOOD AND DRUG ADMINISTRATION (FDA) SINCE 2017. EXPERIMENTAL CAR T CELL THERAPIES HAVE ALSO DEMONSTRATED COMPLETE REMISSIONS IN SOLID TUMORS, AND THE FDA IS PROJECTING TO GRANT 10-15 APPROVALS PER YEAR BY 2025, HIGHLIGHTING THE POTENTIAL OF THESE 'LIVING THERAPIES'. DESPITE THIS, CURRENT CAR T CELL DESIGNS HAVE NOT YET MEDIATED SUSTAINED EFFICACY IN SOLID TUMORS, AND ONLY 30-50% OF B CELL LEUKEMIA AND LYMPHOMA PATIENTS EXPERIENCE LONG-TERM DISEASE CONTROL. TO DEVELOP SAFE AND POTENT NEXT-GENERATION CAR T CELL THERAPIES, IT IS CRITICAL TO UNDERSTAND WHY EXISTING CAR T CELLS SUCCEED OR FAIL IN PATIENTS. AS A SCIENTIST TRAINED IN BOTH EXPERIMENTAL AND COMPUTATIONAL IMMUNO-ONCOLOGY, I HAVE CHOSEN TO FOCUS MY CAREER ON USING A SYSTEMS BIOLOGY APPROACH TO UNCOVER THE MOLECULAR MECHANISMS GOVERNING EFFICACY OF ENGINEERED T CELL IMMUNOTHERAPIES. THIS PROPOSAL OUTLINES A STRUCTURED 2-YEAR TRAINING PLAN AND A COMPREHENSIVE 5-YEAR CAREER DEVELOPMENT PROGRAM TO COMPLETE MY TRAINING AND LAUNCH AN INDEPENDENT RESEARCH CAREER. MY SPECIFIC RESEARCH GOALS ARE: (1) TO DEFINE THE MOST THERAPEUTICALLY RELEVANT CAR T CELL SUBSETS IN PATIENTS WITH LARGE B CELL LYMPHOMA (LBCL), AND (2) TO OVERCOME AN IMMUNE SUPPRESSION MECHANISM OF RESISTANCE TO CAR T CELL THERAPY FOR LBCL. FIRST, I WILL FOLLOW INDIVIDUAL CAR T CELL CLONES THROUGH TIME IN PATIENTS TREATED FOR LBCL USING MATCHED SINGLE-CELL SEQUENCING OF TRANSCRIPTOME, A PANEL OF SURFACE PROTEINS, AND ENDOGENOUS T CELL RECEPTORS (AIM 1). THIS APPROACH, TERMED REVERSE FATE MAPPING, WILL PINPOINT T CELL CLONES IN THE PRE-MANUFACTURE APHERESIS AND INFUSION PRODUCTS WITH SOUGHT-AFTER PROPERTIES, INCLUDING ABILITIES TO EXPAND, PERSIST, AND HOME TO THE TUMOR. IN AIM 2, I WILL APPLY REVERSE FATE MAPPING AND METHYLATION ANALYSES TO IDENTIFY THE ORIGIN OF CIRCULATING CAR T REGULATORY (TREG) CELLS THAT I RECENTLY LINKED TO LIMITED CAR T CELL EFFICACY IN LBCL. IN AIM 3, I WILL MECHANISTICALLY DISSECT THE INTERPLAY BETWEEN TREG AND NON-TREG CAR T CELLS TO DESIGN A POTENT 'TREG-FREE' CAR T CELL THERAPY FOR CLINICAL EVALUATION. MY WORK WILL GENERATE A COMPREHENSIVE CAR T CELL ATLAS AND INSIGHTS, LEADING TO PROMISING AVENUES FOR ENGINEERING THE NEXT-GENERATION CAR T CELL THERAPIES. THE RESULTS OF MY PROPOSED RESEARCH WILL POSITIVELY IMPACT PUBLIC HEALTH, AS THEY WILL GATHER SUFFICIENT PRELIMINARY DATA FOR TESTING A 'TREG-FREE' CD19-CAR T CELL THERAPY FOR LBCL IN A CLINICAL TRIAL AND WILL DELIVER FUNDAMENTAL INSIGHTS INTO CAR TREG BIOLOGY THAT MAY GENERALIZE TO OTHER DISEASES, INCLUDING SOLID TUMORS, WHERE ENGINEERED T CELL THERAPIES HAVE NOT MANIFESTED SIMILARLY POTENT EFFECTS AS IN LBCL. TO BUILD UPON MY SKILLS, I HAVE ASSEMBLED A MENTORSHIP TEAM, INCLUDING MY PRIMARY MENTOR, DR. CRYSTAL MACKALL, A PIONEER IN CAR T CELL IMMUNOTHERAPIES; CO-MENTOR, DR. SYLVIA PLEVRITIS, A LEADER IN CANCER SYSTEMS BIOLOGY; AND AN ADVISORY COMMITTEE WITH EXTENSIVE EXPERTISE RELEVANT TO ALL ASPECTS OF THIS PROPOSAL. THE COMPLETION OF THIS K99/R00 PROGRAM WILL PREPARE ME TO COMPETE FOR R01 FUNDING AND TO LAUNCH AN INDEPENDENT RESEARCH CAREER FOCUSED ON IMPROVING IMMUNOTHERAPIES FOR PATIENT WITH CANCER.
$232.9k 2/13/25