Project Grant R61NS128191

DEVELOPMENT OF MURINE GLIOBLASTOMA MODEL FOR ONCOLYTIC HSV THERAPY - THE OVERALL GOAL OF THIS PROJECT IS TO CREATE A MURINE-MODELS FOR GRADE IV BRAIN TUMORS THAT WILL BE SENSITIVE TO HSV-1 INFECTION AND CAN BE UTILIZED TO EVALUATE ONCOLYTIC HSV-1 (OHSV) DERIVED VIRUSES UTILITY AND SAFETY FOR GRADE IV BRAIN TUMORS. GRADE IV PRIMARY BRAIN TUMORS ARE ASSOCIATED WITH A VERY POOR PROGNOSIS, AND DESPITE SURGERY AND USE OF CHEMOTHERAPY, RADIOTHERAPY AND TUMOR TREATING FIELD DELIVERING DEVICES PATIENT SURVIVAL REMAINS DISMAL. HENCE THERE IS AN URGENT NEED FOR ALTERNATIVE THERAPIES. ONCOLYTIC HSV-1 BASED VIRAL THERAPY (OHSV) IS A PROMISING BIOLOGICAL THERAPY FOR SOLID TUMOR. OHSV IS CURRENTLY APPROVED FOR TREATMENT OF METASTATIC MELANOMA IN USA AND EUROPE. ANOTHER OHSV RECENTLY WAS GIVEN CONDITIONAL APPROVAL FOR TREATMENT OF RECURRENT GBM IN JAPAN. SEVERAL OHSV ARE CURRENTLY BEING INVESTIGATED FOR SAFETY AND EFFICIENCY FOR BRAIN TUMORS INCLUDE G207, HSV1716, M032 AND RQUESTIN34.5. ADDITIONAL DEVELOPMENT OF NOVEL AND SECOND-GENERATION VIRUSES IS ALSO ACTIVELY BEING PURSUED IN MANY LABORATORIES. HOWEVER, THE SPECIES-SPECIFIC NATURE OF VIRUS AND HOST INTERACTIONS PRESENTS A CHALLENGE IN CURRENTLY AVAILABLE MURINE MODELS. THUS A MOUSE MODEL THAT IS IMMUNE COMPETENT, PRODUCES REPRODUCIBLE TUMORS, AND IS PERMISSIVE TO HSV-1 WOULD HELP EXPEDITE SAFETY AND EFFICACY TESTING OF THIS NEW AND PROMISING BIOTHERAPY. AN ANIMAL MODEL THAT IS IMMUNE COMPETENT, PERMISSIVE TO HSV-1, NOT OVERLY IMMUNOGENIC, AND SHOWS REPRODUCIBLE AND EFFICIENT TUMOR GROWTH WOULD BE IDEAL TO TEST OHSV BASED BIOTHERAPIES. HERE WE PROPOSE TO CREATE AN ANIMAL MODEL RECAPITULATES THE EFFECT OF HSV-1 ON TUMOR CELLS AND THE IMMUNE ENVIRONMENT BUT STILL HAS AN ECM ENVIRONMENT CONSISTING OF MICROGLIA, ENDOTHELIAL CELLS ETC. THAT ARE ALSO PERMISSIVE. A SYNGENEIC MURINE GBM MODEL, THAT IS PERMISSIVE TO HSV-1 INFECTION WITHOUT BEING OVERLY IMMUNOGENIC AND SHOWS A 100% TUMOR TAKE IN MICE UPON TRANSPLANTATION WOULD BE IDEAL. WE HAVE CREATED TRANSGENIC MICE THAT EXPRESS HUMAN NECTIN-1 TO PERMIT EFFICIENT VIRUS ENTRY. WE WILL USE NSC FROM THESE MICE TO CREATE BRAIN TUMOR CELLS THAT MIMIC HUMAN BRAIN TUMOR GENETIC ALTERATIONS AND EVALUATE THEM FOR TUMOR TAKE AND RESPONSE TO OHSV THERAPY.