Project Grant R21CA289134

MUC1-C IS A TARGET FOR ADVANCING IMMUNOTHERAPY OF NON-SMALL CELL LUNG CANCER - PROJECT SUMMARY IMMUNE CHECKPOINT INHIBITORS (ICIS), PARTICULARLY THOSE BLOCKING THE PD-1/PD-L1 PATHWAY, HAVE IMPROVED THE TREATMENT OF NON-SMALL CELL LUNG CANCER (NSCLC), SUPPORTING THE PREMISE THAT EVASION OF IMMUNE DESTRUCTION CONTRIBUTES TO NSCLC PATHOGENESIS. NONETHELESS, NSCLCS WITH EGFR MUTATIONS OFTEN EXHIBIT INTRINSIC OR ACQUIRED RESISTANCE TO ICIS, EMPHASIZING A CRITICAL NEED FOR DEFINING THE MECHANISMS THAT DRIVE IMMUNE EVASION AND DEVELOPING AGENTS TO CIRCUMVENT THEM. WORK IN GENETICALLY ENGINEERED MOUSE MODELS (GEMMS) HAS DEMONSTRATED THAT EGFR MUTANT NSCLC CELLS ACTIVATE THE PD-1/PD-L1 PATHWAY AND INCREASE PRODUCTION OF PROINFLAMMATORY CYTOKINES THAT SUPPRESS T CELL ACTIVITY IN THE TUMOR MICROENVIRONMENT (TME). AS A MECHANISTIC BASIS FOR THOSE FINDINGS, WE FOUND THAT THE ONCOGENIC MUC1-C PROTEIN, WHICH IS OF IMPORTANCE FOR NSCLC PROGRESSION, CONTRIBUTES TO INDUCTION OF PD-L1 EXPRESSION AND A PROGRAM OF IMMUNE SUPPRESSION. OTHER STUDIES SHOWED THAT TARGETING MUC1-C IN IMMUNOCOMPETENT NSCLC TUMOR MODELS REVERSES THE SUPPRESSION OF IMMUNE RECOGNITION AND DESTRUCTION. THESE FINDINGS HAVE COLLECTIVELY SUPPORTED THE PREMISE THAT MUC1-C CONTRIBUTES TO AN IMMUNOSUPPRESSIVE NSCLC TME AND IS A POTENTIAL TARGET FOR ADVANCING NSCLC TREATMENT. ACCORDINGLY, WE GENERATED NOVEL ANTIBODIES AGAINST THE NON-SHED MUC1-C EXTRACELLULAR DOMAIN THAT ARE UNDER DEVELOPMENT AS ANTIBODY-DRUG CONJUGATES (ADCS). WHAT IS NEEDED NOW, AT LEAST IN PART, IS TO MORE PRECISELY DEFINE HOW MUC1-C PROMOTES IMMUNE EVASION TO ADVANCE THE IMMUNOTHERAPY OF EGFR MUTANT NSCLCS AND TO DETERMINE WHETHER TARGETING MUC1-C IS EFFECTIVE IN REVERSING IMMUNE SUPPRESSION AND RESISTANCE TO ICIS IN NSCLC TREATMENT. THE AIM OF THIS PROPOSAL IS TO IDENTIFY NOVEL THERAPEUTIC STRATEGIES USING ANTI-MUC1-C ADCS ALONE AND IN COMBINATION WITH ICIS THAT RESTRAIN THE PROGRESSION OF NSCLC THROUGH ACTIVATING ANTI-TUMOR IMMUNITY. OUR OVERALL HYPOTHESIS IS THAT MUC1-C PLAYS AN IMPORTANT ROLE IN IMMUNE EVASION OF EGFR MUTANT NSCLCS, WHICH WILL BE ADDRESSED IN STUDIES OF (I) HUMAN NSCLC CELL LINES, (II) GEMMS, AND (III) NSCLC TUMOR SPECIMENS. THE OBJECTIVE OF THE PROPOSED WORK IS TO ADVANCE OUR UNDERSTANDING OF HOW MUC1-C ACTIVATES IMMUNOSUPPRESSIVE PATHWAYS IN EGFR MUTANT NSCLC BY TARGETING MUC1-C WITH ADCS THAT, BASED ON OUR PRELIMINARY FINDINGS, COULD PROVIDE NEW OPPORTUNITIES FOR IMPROVING NSCLC IMMUNOTHERAPY.