Project Grant F30CA290816

EVALUATING ANTIGEN SPREAD AFTER CDC1 VACCINATION - PROJECT SUMMARY TYPE 1 CONVENTIONAL DENDRITIC CELL (CDC1) VACCINATION IS A NOVEL PRE-CLINICAL CELL THERAPY THAT ELICITS SYSTEMIC IMMUNITY IN SEVERAL MURINE TUMOR MODELS, INCLUDING MELANOMA, AND AUGMENTS RESPONSE TO IMMUNE CHECKPOINT BLOCKADE (ICB). CDC1S POSSESS THE ABILITY TO CROSS-PRESENT TUMOR ANTIGEN TO CD8+ T CELLS, MIGRATE FROM TUMORS TO TUMOR-DRAINING LYMPH NODES, AND ENHANCE NAIVE CD8+ T CELL PRIMING; HOWEVER, MECHANISMS BY WHICH CDC1S ELICIT EFFECTIVE ANTI-TUMOR CD8+ T CELL RESPONSES IN THE CONTEXT OF VACCINATION REMAIN UNCLEAR. MY PROJECT WILL EXPLORE THE POTENTIAL OF CDC1 VACCINATION ALONE AND IN COMBINATION WITH ACTLA4 ICB TO GENERATE DIVERSE AND EFFECTIVE CD8+ T CELL RESPONSES. SPECIFICALLY, I WILL STUDY THE ABILITY OF CDC1S TO INDUCE ANTIGEN SPREAD, WHICH IS DEFINED AS INDUCTION AND EXPANSION OF T CELL CLONES THAT WERE NOT A DIRECT TARGET OF OR PRESENT IN THE INITIAL TARGETED THERAPY. IMPORTANTLY, ANTIGEN SPREAD HAS BEEN OBSERVED IN PATIENTS RESPONSIVE TO IMMUNOTHERAPY AND MAY PRESENT AN OPPORTUNITY TO COUNTERACT TUMOR ANTIGEN LOSS THAT CAN OCCUR DURING TUMOR EVOLUTION. IT IS THOUGHT TO OCCUR AFTER TUMOR ANTIGENS, RELEASED FROM DYING TUMOR CELLS, ARE PHAGOCYTOSED BY ANTIGEN PRESENTING CELLS (APCS) AND CROSS-PRESENTED TO NAIVE T CELLS TO STIMULATE THEIR ACTIVATION. IN ADDITION, CTLA4 BLOCKADE CAN INDUCE ANTIGEN SPREAD BY PROMOTING T CELL COSTIMULATION AND LOWERING THE ACTIVATION THRESHOLD FOR NAIVE T CELLS DURING PRIMING. THE SPECIALIZED FUNCTIONS OF CDC1S CREATE AN IDEAL SETTING TO STUDY ANTIGEN SPREAD. MY PROJECT INVESTIGATES THE ABILITY OF A TARGET-ANTIGEN-LOADED CDC1 VACCINE ALONE AND WITH ACTLA4 TO CONTROL TARGET ANTIGEN- EXPRESSING (ANTIGEN-POSITIVE) AND TARGET ANTIGEN NON-EXPRESSING (ANTIGEN-NEGATIVE) TUMORS USING B16F10 AND YUMM1.7 MURINE MELANOMA LINES EXPRESSING OVALBUMIN (B16F10) AND MLAMA4 AND MITGB1 (YUMM1.7) AS TARGET ANTIGENS. I HYPOTHESIZE THAT CDC1 VACCINATION ELICITS ANTIGEN SPREAD, AND THAT COMBINATION TREATMENT WITH CDC1 VACCINATION AND ACTLA4 FURTHER POTENTIATES TUMOR CONTROL THROUGH INCREASING CD8+ T CELL DIVERSITY. IN AIM 1, I WILL TEST THE HYPOTHESIS THAT THE TARGET ANTIGEN-LOADED CDC1 VACCINE WILL CONTROL TARGET ANTIGEN-POSITIVE AND TARGET ANTIGEN-NEGATIVE TUMORS, AND THAT CDC1S ENHANCE ACTLA4 EFFICACY AGAINST TARGET ANTIGEN-NEGATIVE TUMORS BY ENHANCING THE QUANTITY AND QUALITY OF THE CD8+ T CELL RESPONSE. IN AIM 2, I WILL TEST THE HYPOTHESIS THAT CDC1 VACCINATION WITH ACTLA4 WILL RESULT IN THE MOST DIVERSE CD8+ EFFECTOR T CELL REPERTOIRE, AND THAT CDC1 VACCINATION ELICITS A CD8+ T CELL TRANSCRIPTIONAL STATE THAT PROMOTES TUMOR CONTROL. THE WATOWICH AND YEE LABORATORIES AT MD ANDERSON PROVIDE THE IDEAL ENVIRONMENT TO CONDUCT MY PROPOSED STUDIES, AS I WILL LEARN CUTTING-EDGE IMMUNOTHERAPY TECHNIQUES, STRENGTHEN MY FUNDAMENTAL IMMUNOLOGY KNOWLEDGE, AND ACQUIRE PERTINENT BIOINFORMATICS ANALYSIS SKILLS UNDER THE DIRECT GUIDANCE OF MY MENTORS. THIS TRAINING ENVIRONMENT WILL AFFORD ME THE CHANCE TO LEARN FROM WORLD LEADERS IN TUMOR IMMUNOLOGY AND GRANT ACCESS TO STATE-OF-THE-ART FACILITIES AND RESOURCES THAT ARE INTEGRAL TO MY FURTHER DEVELOPMENT OF MY CAREER AS A PHYSICIAN-SCIENTIST.