Project Grant R01CA283580

NOVEL GENE DELIVERY TO MODULATE THE TUMOR MICROENVIRONMENT AND ANTIGEN-SPECIFIC ANTITUMOR IMMUNITY - ABSTRACT TECHNOLOGICAL ADVANCEMENTS HAVE YIELDED NOVEL DRUG TARGETS AND IMPROVED CANCER DETECTION, BUT TRANSFORMATIVE INNOVATIONS IN TREATMENT MODALITIES ARE LACKING. LEVERAGING OUR TEAM'S EXPERTISE IN GENE THERAPY, BREAST CANCER, CANCER IMMUNOLOGY, AND BREAST CANCER ANIMAL AND PATIENT-DERIVED XENOGRAFT MODELS, WE PROPOSE TO USE RECOMBINANT ADENOVIRUS WITH A HIGHER TUMOR-SPECIFIC EXPRESSION OF HERPES SIMPLEX VIRUS-THYMIDINE KINASE (HSV-TK), WHICH IS A SUICIDE GENE THAT CAUSES TUMOR CELL DEATH. WE WILL COMBINE HSV-TK WITH OUR IMMUNE CHECKPOINT ANTIBODY (I.E. HMR-101) THAT WILL SPECIFICALLY TARGET TUMOR CELLS, RELEASE TUMOR ANTIGENS AND CHANGE THE TUMOR MICROENVIRONMENT TO BE MORE FAVORABLE FOR IMMUNE THERAPY. THE IMMUNOTHERAPY WE ARE DEVELOPING WILL MODIFY CANCER-PROMOTING IMMUNE CELLS TO BECOME ANTI-CANCER IMMUNE CELLS. THEREFORE, AN ARMY OF ANTI-CANCER IMMUNE CELLS TRAINED TO RECOGNIZE CANCEROUS CELLS WILL MOBILIZE AND CIRCULATE AROUND THE BODY TO DESTROY METASTASES. GIVEN THE PREDOMINANCE OF TUMOR-ASSOCIATED IMMUNOSUPPRESSIVE MYELOID CELLS IN TRIPLE-NEGATIVE BREAST CANCER, LOCAL DELIVERY OF HMR-101 COULD EFFECTIVELY REPROGRAM THE TUMOR MICROENVIRONMENT TO AN ANTI-TUMOR IMMUNE PHENOTYPE. THE VIRAL TRANSDUCTION EFFICIENCY OF OUR VIRAL VECTOR IS VERY HIGH AT THE TUMOR SITE WITH CHIMERIC VIRAL VECTOR (LOW NEUTRALIZATION ANTIBODY), AND IT WILL BE LOW SPREADING TO OTHER ORGANS. THIS VIRAL VECTOR IS SAFE AND APPROVED BY THE FDA AND AT LOW COST FOR HUMAN USE. AS SUCH, OUR INTRATUMORAL STRATEGY WOULD ALLOW FOR MAXIMIZING THE FULL POTENCY OF THE IMMUNOTHERAPEUTIC ANTIBODY, THUS ENHANCING THERAPEUTIC INDEX. WE ENVISION THIS TECHNOLOGY TO MOVE FORWARD TO CLINICAL TRIALS, STRONGLY SUPPORTED BY THE SUCCESS OF OUR RECENTLY COMPLETED STOMP TRIAL FOR METASTATIC TRIPLE-NEGATIVE BREAST CANCER OR TNBC (NCT03004183, HSV-TK, RADIATION, AND IMMUNE CHECKPOINT THERAPY ON METASTATIC TNBC). CLINICALLY, WE ENVISION THAT OUR INTRATUMOR GENE DELIVERY OF HMR-101 WILL REPROGRAM THE IMMUNE SYSTEM, PREVENT PATIENTS FROM RELAPSE, AND PROLONG ANTI-TUMOR IMMUNITY, THUS BENEFITING PATIENTS RECEIVING IMMUNOTHERAPY. FOR TRIPLE-NEGATIVE BREAST CANCER PATIENTS WHO TYPICALLY HAVE DISMAL CLINICAL RESPONSE DUE TO HIGH METASTATIC RATE AND RECURRENCE, THE POTENTIAL CLINICAL IMPACT OF OUR INTRATUMORAL VIRAL DELIVERY CONTAINING NOVEL IMMUNE CHECKPOINT ANTIBODY IS PROFOUND. OVERALL, THE THERAPEUTIC REACH OF OUR NOVEL THERAPEUTIC REGIMEN IS EXPANSIVE, OFFERING A TRULY TRANSFORMATIVE APPROACH TO CANCER TREATMENT.