Project Grant R44CA257278

CLINICAL EVALUATION OF A PERSONALIZED VACCINE IMMUNOTHERAPY IN COMBINATION WITH CHECKPOINT INHIBITORS FOR TRIPLE NEGATIVE BREAST CANCER - ABSTRACT OF THE SUPPLEMENTAL GRANT: BREAST CANCER ACCOUNTS FOR THE HIGHEST CANCER-RELATED MORTALITY IN WOMEN. AMONG ITS SUBTYPES, METASTATIC TRIPLE NEGATIVE BREAST CANCER (TNBC) HAS THE WORST PROGNOSIS LARGELY DUE TO RESISTANCE TO CURRENTLY AVAILABLE THERAPIES AND LACK OF ESTROGEN RECEPTOR, PROGESTERONE RECEPTOR AND HER-2 PROTEIN EXPRESSION. RECENT STUDIES EMPLOYING IMMUNE CHECKPOINT INHIBITOR (ICI) THERAPIES SUGGEST THAT TNBC MAY BE A GOOD TARGET FOR ICI THERAPY DUE TO THE PRESENCE OF HIGH LEVEL OF INFILTRATING LYMPHOCYTES. HOWEVER, THE MAJORITY OF THE TNBC CANCER PATIENTS DO NOT RESPOND TO ICI THERAPY DUE TO THE LACK OF PRE-EXISTING IMMUNITY. IN ORDER TO DEVELOP MORE EFFECTIVE TREATMENTS, IT IS IMPORTANT TO DESIGN A THERAPEUTIC APPROACH FOR TNBC PATIENTS WHICH OVERCOMES INTRA-TUMORAL AND INTER-PATIENT HETEROGENEITY. METACLIPSE THERAPEUTICS HAS BEEN ENGAGED IN DEVELOPING A PERSONALIZED VACCINE TO ADDRESS HETEROGENEITY. UTILIZING A NOVEL PROTEIN TRANSFER METHOD, WE GENERATE TUMOR MEMBRANE VESICLES (TMVS) DERIVED FROM WHOLE TUMOR TISSUES AND MODIFY THEM WITH GLYCOLIPID-ANCHORED FORMS OF IMMUNOSTIMULATORY MOLECULES (GPI- ISMS) EXPRESSING B7-1 AND INTERLEUKIN-12 (IL-12). OUR DATA DEMONSTRATES THAT TMV VACCINES PREPARED FROM SYNGENEIC TUMORS ARE EFFECTIVE IN MULTIPLE MURINE MODELS OF CANCER. HOWEVER, IT IS CURRENTLY UNKNOWN IF NEOADJUVANT CHEMOTHERAPY WHICH IS A STANDARD OF CARE FOR BREAST CANCER AFFECTS THE YIELD AND QUALITY OF TMV- BASED VACCINES. WE HYPOTHESIZE THAT THE ADDITION OF STANDARD-OF-CARE (SOC) CHEMOTHERAPY WHICH IS USUALLY ADMINISTERED IN TNBC PATIENTS BEFORE SURGERY IMPACTS THE YIELD AND QUALITY OF TMV-BASED VACCINES. TO ADDRESS THIS, THE FOLLOWING SPECIFIC AIMS ARE PROPOSED. AIM 1, TO DEFINE THE IMPACT OF NEOADJUVANT CHEMOTHERAPY ON THE YIELD AND QUALITY OF THE TMV VACCINE. AIM 2, TO DEFINE THE IMPACT OF NEOADJUVANT CHEMOTHERAPY ON THE ABILITY OF TMV VACCINE TO STIMULATE APCS AND AUTOLOGOUS T CELLS EX VIVO. THE PARENT GRANT OF THIS SUPPLEMENT PROPOSAL WILL BE CONDUCTING PHASE 1 CLINICAL TRIAL TO EVALUATE THE TOLERABILITY OF TMV VACCINE IN TNBC PATIENTS. THIS STUDY WILL PROVIDE AN UNDERSTANDING ABOUT HOW THE NEOADJUVANT CHEMOTHERAPY IMPACTS THE TMV-BASED VACCINES PREPARED FROM TNBC TUMORS.