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CLINICAL EVALUATION OF A PERSONALIZED VACCINE IMMUNOTHERAPY IN COMBINATION WITH CHECKPOINT INHIBITORS FOR TRIPLE NEGATIVE BREAST CANCER - PROJECT SUMMARY TRIPLE NEGATIVE BREAST CANCER (TNBC) IS AN AGGRESSIVE TYPE OF BREAST CANCER WITH LIMITED EFFECTIVE THERAPIES. EACH YEAR MORE THAN 40,000 NEW CASES OF TNBC ARE DIAGNOSED IN THE US ALONE. TNBC INCLUDES BREAST CAN- CERS THAT LACK ESTROGEN RECEPTOR (ER), PROGESTERONE RECEPTOR (PR), AND HUMAN EPIDERMAL GROWTH FACTOR RECEP- TOR 2 (HER-2) OVEREXPRESSION. LACK OF KNOWN TARGETS AND PATIENT-TO-PATIENT VARIATION OF TARGET ANTIGENS MAKE TNBC ONE OF THE MOST CHALLENGING CANCERS FOR DEVELOPING AN EFFECTIVE THERAPY. TNBC IS ALSO GENERALLY RE- SISTANT TO THE IMMUNE CHECKPOINT INHIBITORS (ICI) SUGGESTING THE NEED FOR NOVEL THERAPIES. WE PROPOSE TO EVAL- UATE A NOVEL VACCINE IMMUNOTHERAPY ADMINISTERED ALONE OR IN COMBINATION WITH ICI TO TREAT METASTATIC TNBC. METACLIPSE’S IMMUNOTHERAPY (AUTOLOGOUS THERAPEUTIC VACCINE) CONSISTS OF TUMOR MEMBRANE VESICLES (TMVS) MADE FROM PATIENT-SPECIFIC TUMOR TISSUE, WHICH CARRY TUMOR ANTIGENS INCLUDING MEMBRANE-ASSOCIATED PROTEIN AND CARBOHYDRATE ANTIGENS, AND ANTIGENIC PEPTIDES DERIVED FROM CYTOSOLIC PROTEINS AS MHC-ASSOCIATED PEP- TIDES. THESE TMVS ARE THEN DIRECTLY CONJUGATED TO POTENT GLYCOLIPID-ANCHORED IMMUNOSTIMULATORY MOLECULES (GPI-ISMS) BY A NOVEL PROTEIN TRANSFER TECHNOLOGY. THE NOVELTY OF THE PROPOSED VACCINE LIES NOT IN THE USE OF ISMS, BUT THE WAY THEY ARE EMPLOYED. THIS DIRECT PHYSICAL LINKAGE OF TMVS AND GPI-ISMS ALLOWS FOR SIMULTA- NEOUS DELIVERY OF THE PATIENT’S UNIQUE TUMOR ANTIGEN SIGNATURE AND ISMS AT THE VACCINATION SITE TO INDUCE A RO- BUST ANTI-TUMOR IMMUNE RESPONSE. SINCE THE TMV VACCINE IS PREPARED FROM WHOLE TUMOR TISSUE, IT ENCOM- PASSES NOT ONLY PATIENT-SPECIFIC VARIATION BUT ALSO ALL OF THE HETEROGENEITY OF THE TUMORS. A KEY ADVANTAGE OF OUR APPROACH IS THAT THE IMMUNOTHERAPY PRODUCT CAN BE PREPARED IN LESS THAN 14 DAYS, WHICH IS CRITICAL DURING TREATMENT OF AGGRESSIVE CANCERS SUCH AS TNBC. THE COMPANY HAS SUCCESSFULLY COMPLETED PRECLINICAL STUDIES USING ICI-RESISTANT PRECLINICAL MOUSE MODELS INCLUDING TNBC. THE RESULTS DEMONSTRATE THAT IMMUNIZATION WITH TMV VACCINE SENSITIZES THE ICI-RESISTANT 4T1 TNBC TO BECOME RESPONSIVE TO ICI THERAPY. IN ADDITION, GLP TOX- ICOLOGY STUDIES IN MICE DEMONSTRATED THE SAFETY OF THE VACCINE, EVEN AT A 5X DOSE IN COMBINATION WITH ICI THER- APY. FURTHERMORE, WE HAVE ESTABLISHED: (1) STABLE CGMP-COMPLIANT CHO CELL CLONES EXPRESSING THE HUMAN GPI-PROTEINS, (2) SOPS FOR THE CGMP-COMPLIANT PRODUCTION AND PURIFICATION OF THE GPI-ANCHORED PROTEINS, AND (3) SOPS FOR PROCESSING OF SAMPLES FROM HUMAN TNBC TUMORS TO GENERATE TMV VACCINE. THE SBIR DIRECT PHASE II PROPOSAL IS AIMED AT TRANSLATING THIS TECHNOLOGY TO THE CLINIC. THE FOLLOWING SPECIFIC AIMS ADDRESS THE OVERALL GOALS OF THE PROPOSAL: (1) CGMP MANUFACTURING OF DRUG SUBSTANCE; (2) A PHASE 1A/B CLINICAL TRIAL TO ES- TABLISH SAFETY AND IMMUNE RESPONSE, AS WELL AS PRELIMINARY INDICATION OF EFFICACY OF THE VACCINE ALONE AND IN COMBINATION WITH IMMUNE CHECKPOINT INHIBITORS (ICI). THE PROPOSED PLAN REPRESENTS METACLIPSE’S CRITICAL PATH TO INITIATE AND COMPLETE A PHASE 1A/B CLINICAL TRIAL. SUCCESSFUL COMPLETION OF THESE AIMS WILL ADVANCE OUR UNIQUE PERSONALIZED VACCINE IMMUNOTHERAPY PLATFORM CLOSER TO TREATING TNBC PATIENTS WHO CURRENTLY DO NOT HAVE EF- FECTIVE TREATMENT OPTIONS DUE TO THE HIGHLY HETEROGENOUS NATURE OF THE DISEASE.

CLINICAL EVALUATION OF A PERSONALIZED VACCINE IMMUNOTHERAPY IN COMBINATION WITH CHECKPOINT INHIBITORS FOR TRIPLE NEGATIVE BREAST CANCER - PROJECT SUMMARY TRIPLE NEGATIVE BREAST CANCER (TNBC) IS AN AGGRESSIVE TYPE OF BREAST CANCER WITH LIMITED EFFECTIVE THERAPIES. EACH YEAR MORE THAN 40,000 NEW CASES OF TNBC ARE DIAGNOSED IN THE US ALONE. TNBC INCLUDES BREAST CAN- CERS THAT LACK ESTROGEN RECEPTOR (ER), PROGESTERONE RECEPTOR (PR), AND HUMAN EPIDERMAL GROWTH FACTOR RECEP- TOR 2 (HER-2) OVEREXPRESSION. LACK OF KNOWN TARGETS AND PATIENT-TO-PATIENT VARIATION OF TARGET ANTIGENS MAKE TNBC ONE OF THE MOST CHALLENGING CANCERS FOR DEVELOPING AN EFFECTIVE THERAPY. TNBC IS ALSO GENERALLY RE- SISTANT TO THE IMMUNE CHECKPOINT INHIBITORS (ICI) SUGGESTING THE NEED FOR NOVEL THERAPIES. WE PROPOSE TO EVAL- UATE A NOVEL VACCINE IMMUNOTHERAPY ADMINISTERED ALONE OR IN COMBINATION WITH ICI TO TREAT METASTATIC TNBC. METACLIPSE’S IMMUNOTHERAPY (AUTOLOGOUS THERAPEUTIC VACCINE) CONSISTS OF TUMOR MEMBRANE VESICLES (TMVS) MADE FROM PATIENT-SPECIFIC TUMOR TISSUE, WHICH CARRY TUMOR ANTIGENS INCLUDING MEMBRANE-ASSOCIATED PROTEIN AND CARBOHYDRATE ANTIGENS, AND ANTIGENIC PEPTIDES DERIVED FROM CYTOSOLIC PROTEINS AS MHC-ASSOCIATED PEP- TIDES. THESE TMVS ARE THEN DIRECTLY CONJUGATED TO POTENT GLYCOLIPID-ANCHORED IMMUNOSTIMULATORY MOLECULES (GPI-ISMS) BY A NOVEL PROTEIN TRANSFER TECHNOLOGY. THE NOVELTY OF THE PROPOSED VACCINE LIES NOT IN THE USE OF ISMS, BUT THE WAY THEY ARE EMPLOYED. THIS DIRECT PHYSICAL LINKAGE OF TMVS AND GPI-ISMS ALLOWS FOR SIMULTA- NEOUS DELIVERY OF THE PATIENT’S UNIQUE TUMOR ANTIGEN SIGNATURE AND ISMS AT THE VACCINATION SITE TO INDUCE A RO- BUST ANTI-TUMOR IMMUNE RESPONSE. SINCE THE TMV VACCINE IS PREPARED FROM WHOLE TUMOR TISSUE, IT ENCOM- PASSES NOT ONLY PATIENT-SPECIFIC VARIATION BUT ALSO ALL OF THE HETEROGENEITY OF THE TUMORS. A KEY ADVANTAGE OF OUR APPROACH IS THAT THE IMMUNOTHERAPY PRODUCT CAN BE PREPARED IN LESS THAN 14 DAYS, WHICH IS CRITICAL DURING TREATMENT OF AGGRESSIVE CANCERS SUCH AS TNBC. THE COMPANY HAS SUCCESSFULLY COMPLETED PRECLINICAL STUDIES USING ICI-RESISTANT PRECLINICAL MOUSE MODELS INCLUDING TNBC. THE RESULTS DEMONSTRATE THAT IMMUNIZATION WITH TMV VACCINE SENSITIZES THE ICI-RESISTANT 4T1 TNBC TO BECOME RESPONSIVE TO ICI THERAPY. IN ADDITION, GLP TOX- ICOLOGY STUDIES IN MICE DEMONSTRATED THE SAFETY OF THE VACCINE, EVEN AT A 5X DOSE IN COMBINATION WITH ICI THER- APY. FURTHERMORE, WE HAVE ESTABLISHED: (1) STABLE CGMP-COMPLIANT CHO CELL CLONES EXPRESSING THE HUMAN GPI-PROTEINS, (2) SOPS FOR THE CGMP-COMPLIANT PRODUCTION AND PURIFICATION OF THE GPI-ANCHORED PROTEINS, AND (3) SOPS FOR PROCESSING OF SAMPLES FROM HUMAN TNBC TUMORS TO GENERATE TMV VACCINE. THE SBIR DIRECT PHASE II PROPOSAL IS AIMED AT TRANSLATING THIS TECHNOLOGY TO THE CLINIC. THE FOLLOWING SPECIFIC AIMS ADDRESS THE OVERALL GOALS OF THE PROPOSAL: (1) CGMP MANUFACTURING OF DRUG SUBSTANCE; (2) A PHASE 1A/B CLINICAL TRIAL TO ES- TABLISH SAFETY AND IMMUNE RESPONSE, AS WELL AS PRELIMINARY INDICATION OF EFFICACY OF THE VACCINE ALONE AND IN COMBINATION WITH IMMUNE CHECKPOINT INHIBITORS (ICI). THE PROPOSED PLAN REPRESENTS METACLIPSE’S CRITICAL PATH TO INITIATE AND COMPLETE A PHASE 1A/B CLINICAL TRIAL. SUCCESSFUL COMPLETION OF THESE AIMS WILL ADVANCE OUR UNIQUE PERSONALIZED VACCINE IMMUNOTHERAPY PLATFORM CLOSER TO TREATING TNBC PATIENTS WHO CURRENTLY DO NOT HAVE EF- FECTIVE TREATMENT OPTIONS DUE TO THE HIGHLY HETEROGENOUS NATURE OF THE DISEASE.

CLINICAL EVALUATION OF A PERSONALIZED VACCINE IMMUNOTHERAPY IN COMBINATION WITH CHECKPOINT INHIBITORS FOR TRIPLE NEGATIVE BREAST CANCER - PROJECT SUMMARY TRIPLE NEGATIVE BREAST CANCER (TNBC) IS AN AGGRESSIVE TYPE OF BREAST CANCER WITH LIMITED EFFECTIVE THERAPIES. EACH YEAR MORE THAN 40,000 NEW CASES OF TNBC ARE DIAGNOSED IN THE US ALONE. TNBC INCLUDES BREAST CAN- CERS THAT LACK ESTROGEN RECEPTOR (ER), PROGESTERONE RECEPTOR (PR), AND HUMAN EPIDERMAL GROWTH FACTOR RECEP- TOR 2 (HER-2) OVEREXPRESSION. LACK OF KNOWN TARGETS AND PATIENT-TO-PATIENT VARIATION OF TARGET ANTIGENS MAKE TNBC ONE OF THE MOST CHALLENGING CANCERS FOR DEVELOPING AN EFFECTIVE THERAPY. TNBC IS ALSO GENERALLY RE- SISTANT TO THE IMMUNE CHECKPOINT INHIBITORS (ICI) SUGGESTING THE NEED FOR NOVEL THERAPIES. WE PROPOSE TO EVAL- UATE A NOVEL VACCINE IMMUNOTHERAPY ADMINISTERED ALONE OR IN COMBINATION WITH ICI TO TREAT METASTATIC TNBC. METACLIPSE’S IMMUNOTHERAPY (AUTOLOGOUS THERAPEUTIC VACCINE) CONSISTS OF TUMOR MEMBRANE VESICLES (TMVS) MADE FROM PATIENT-SPECIFIC TUMOR TISSUE, WHICH CARRY TUMOR ANTIGENS INCLUDING MEMBRANE-ASSOCIATED PROTEIN AND CARBOHYDRATE ANTIGENS, AND ANTIGENIC PEPTIDES DERIVED FROM CYTOSOLIC PROTEINS AS MHC-ASSOCIATED PEP- TIDES. THESE TMVS ARE THEN DIRECTLY CONJUGATED TO POTENT GLYCOLIPID-ANCHORED IMMUNOSTIMULATORY MOLECULES (GPI-ISMS) BY A NOVEL PROTEIN TRANSFER TECHNOLOGY. THE NOVELTY OF THE PROPOSED VACCINE LIES NOT IN THE USE OF ISMS, BUT THE WAY THEY ARE EMPLOYED. THIS DIRECT PHYSICAL LINKAGE OF TMVS AND GPI-ISMS ALLOWS FOR SIMULTA- NEOUS DELIVERY OF THE PATIENT’S UNIQUE TUMOR ANTIGEN SIGNATURE AND ISMS AT THE VACCINATION SITE TO INDUCE A RO- BUST ANTI-TUMOR IMMUNE RESPONSE. SINCE THE TMV VACCINE IS PREPARED FROM WHOLE TUMOR TISSUE, IT ENCOM- PASSES NOT ONLY PATIENT-SPECIFIC VARIATION BUT ALSO ALL OF THE HETEROGENEITY OF THE TUMORS. A KEY ADVANTAGE OF OUR APPROACH IS THAT THE IMMUNOTHERAPY PRODUCT CAN BE PREPARED IN LESS THAN 14 DAYS, WHICH IS CRITICAL DURING TREATMENT OF AGGRESSIVE CANCERS SUCH AS TNBC. THE COMPANY HAS SUCCESSFULLY COMPLETED PRECLINICAL STUDIES USING ICI-RESISTANT PRECLINICAL MOUSE MODELS INCLUDING TNBC. THE RESULTS DEMONSTRATE THAT IMMUNIZATION WITH TMV VACCINE SENSITIZES THE ICI-RESISTANT 4T1 TNBC TO BECOME RESPONSIVE TO ICI THERAPY. IN ADDITION, GLP TOX- ICOLOGY STUDIES IN MICE DEMONSTRATED THE SAFETY OF THE VACCINE, EVEN AT A 5X DOSE IN COMBINATION WITH ICI THER- APY. FURTHERMORE, WE HAVE ESTABLISHED: (1) STABLE CGMP-COMPLIANT CHO CELL CLONES EXPRESSING THE HUMAN GPI-PROTEINS, (2) SOPS FOR THE CGMP-COMPLIANT PRODUCTION AND PURIFICATION OF THE GPI-ANCHORED PROTEINS, AND (3) SOPS FOR PROCESSING OF SAMPLES FROM HUMAN TNBC TUMORS TO GENERATE TMV VACCINE. THE SBIR DIRECT PHASE II PROPOSAL IS AIMED AT TRANSLATING THIS TECHNOLOGY TO THE CLINIC. THE FOLLOWING SPECIFIC AIMS ADDRESS THE OVERALL GOALS OF THE PROPOSAL: (1) CGMP MANUFACTURING OF DRUG SUBSTANCE; (2) A PHASE 1A/B CLINICAL TRIAL TO ES- TABLISH SAFETY AND IMMUNE RESPONSE, AS WELL AS PRELIMINARY INDICATION OF EFFICACY OF THE VACCINE ALONE AND IN COMBINATION WITH IMMUNE CHECKPOINT INHIBITORS (ICI). THE PROPOSED PLAN REPRESENTS METACLIPSE’S CRITICAL PATH TO INITIATE AND COMPLETE A PHASE 1A/B CLINICAL TRIAL. SUCCESSFUL COMPLETION OF THESE AIMS WILL ADVANCE OUR UNIQUE PERSONALIZED VACCINE IMMUNOTHERAPY PLATFORM CLOSER TO TREATING TNBC PATIENTS WHO CURRENTLY DO NOT HAVE EF- FECTIVE TREATMENT OPTIONS DUE TO THE HIGHLY HETEROGENOUS NATURE OF THE DISEASE.