Project Grant F30CA291027

ICOS IS AN IMPORTANT MEDIATOR OF BOTH RESIDENT MEMORY CELL FORMATION, AND IMPROVED DURABILITY AND PERSISTENCE OF ANTI-TUMOR T CELLS - PROJECT SUMMARY: DESPITE ADVANCES IN IMMUNOTHERAPY, THERE ARE STILL MANY PATIENTS WITH TUMORS THAT DO NOT RESPOND OR RELAPSE AFTER TREATMENT. FOR EXAMPLE, PATIENTS DIAGNOSED WITH METASTATIC MELANOMA HAVE AN OVERALL POOR PROGNOSIS WITH A FIVE-YEAR SURVIVAL OF ONLY 22.5%. ADOPTIVE T CELL TRANSFER (ACT) THERAPY IS A PROMISING APPROACH THAT CAN IMPROVE OUTCOMES. ACT ENCOMPASSES VARIOUS TYPES OF THERAPIES, INCLUDING TUMOR-INFILTRATING LYMPHOCYTES (TIL), T CELLS ENGINEERED TO EXPRESS ANTIGEN-SPECIFIC T CELL RECEPTORS (TCR), AND CHIMERIC ANTIGEN RECEPTOR (CAR) T CELL THERAPIES. THESE THERAPIES INVOLVE INFUSING T CELLS BACK INTO PATIENTS THAT HAVE BEEN MANUFACTURED TO BETTER RECOGNIZE AND REGRESS THE TUMOR. HOWEVER, EVEN WITH THIS THERAPY, THERE ARE PATIENTS WHO DO NOT RESPOND. THUS, THERE IS AN URGENT NEED TO IMPROVE THIS THERAPY. INTERESTINGLY, MY NEW UNPUBLISHED WORK NOW REVEALS THERE IS AN INCREASED NUMBER OF RESIDENT MEMORY T CELLS IN THE SKIN OF MICE WHO RESPONDED TO ACT THERAPY. WHEN WE GIVE ACT TO PATIENTS, T CELLS INITIALLY CIRCULATE IN THE BLOOD, BUT CERTAIN SIGNALING CUES HELP THEM TO BECOME RESIDENT IN TISSUES AND AID IN PROTECTIVE IMMUNITY. THE WORK PROPOSED HEREIN WILL INVESTIGATE THESE SIGNALING CUES, IN PARTICULAR, THE ROLE OF INDUCIBLE COSTIMULATORY MOLECULE (ICOS). ICOS RECEPTOR IS FOUND ON T CELLS AND WHEN BOUND TO ICOS-LIGAND INITIATES A CO-STIMULATORY INTERACTION THAT AIDS THEIR ABILITY TO SECRETE CYTOKINES AND ELICIT ANTITUMOR ACTIVITY. ADDITIONALLY, ICOS IS AN IMPORTANT MEDIATOR OF ANTI-CTLA-4 THERAPY EFFICACY. WE HYPOTHESIZE THAT ICOS SIGNALING INDUCES RESIDENT MEMORY PHENOTYPES IN TH17 CELLS AFTER ADOPTIVE TRANSFER WHEN COMBINED WITH IMMUNE CHECKPOINT BLOCKADE (ICB) AND THAT ICOS, WHEN INCORPORATED AS A CO-STIMULATORY DOMAIN INTO TYROSINASE-RELATED-PEPTIDE (TRP) TARGETING CAR-T CELLS, IMPROVES THE RESIDENCY, PERSISTENCE, AND ANTI-TUMOR EFFICACY IN MICE WITH MELANOMA TUMORS. IN AIM 1, I WILL TEST THE HYPOTHESIS THAT ICOS IS A CRITICAL SIGNALING CUE IN INDUCING TISSUE RESIDENCE OF ANTITUMOR TH17 CELLS IN ANIMALS GIVEN CTLA-4 THERAPY BY (A) INVESTIGATING HOW ICOS INHIBITION AFFECTS LEVELS OF RESIDENT MEMORY TH17 CELL FORMATION IN THE CONTEXT OF ICB AND ACT AND (B) EXAMINING HOW KNOCKING OUT ICOS ON TRANSFERRED T-CELLS AFFECTS THEIR ANTI-TUMOR ABILITIES AND PHENOTYPE. IN AIM 2, I WILL EXPLORE HOW THE INCORPORATION OF ICOS INTO CAR TH17 CELLS AFFECTS THEIR FUNCTION, PHENOTYPE, TRANSCRIPTIONAL PROFILE, AND ANTI-TUMOR ACTIVITY IN AN IMMUNOCOMPETENT MODEL AS WELL AS WHAT THE ROLE OF THE PI3-KINASE PATHWAY IS IN THIS PROCESS. TOGETHER, THESE AIMS WILL PROVIDE FUNDAMENTAL INFORMATION ABOUT THE ROLE OF ICOS CO-STIMULATION ON THE INDUCTION OF RESIDENT MEMORY T CELLS AS WELL AS HOW IT CAN BE INNOVATIVELY USED TO IMPROVE EMERGING CAR T CELL THERAPIES FOR PATIENTS WITH MELANOMA. GAINING THIS UNDERSTANDING WILL FULFILL THE LONG-TERM GOAL OF THIS RESEARCH: TO STUDY SIGNALING PATHWAYS IMPORTANT IN CREATING RESIDENT MEMORY TH17 CELLS AND TO MANIPULATE THESE PATHWAYS TO SEE IF WE CAN IMPROVE EXISTING THERAPY OPTIONS FOR PATIENTS.