Local and distant immune-mediated control of colon cancer growth with fusogenic membrane glycoproteins in combination with viral oncolysis.
We evaluated whether the expression of measles virus fusogenic membrane glycoproteins H and F (MV-FMG), encoded by a herpes simplex virus type 1 (HSV-1) amplicon vector, can serve with or without viral oncolysis (G47Delta) and facultative irinotecan chemotherapy, alone or in combination with the monoclonal epidermal growth factor receptor (EGFR) inhibitory antibody cetuximab, as a platform for inducing tumor-specific immune responses against colon cancer. We demonstrated in vitro that MV-FMG expression in murine cells resulted in cell-cell fusion and synergistically enhanced the cytotoxicity of irinotecan alone or in combination with cetuximab. In a bilateral syngeneic subcutaneous MC38 and Colon26 tumor model in C57BL/6 and BALB/c mice we assessed both the effect on directly vector-treated tumors and the effect on contralateral, not directly vector-treated tumors. We demonstrated that the combination of three treatment components with or without cetuximab resulted in the best volume reduction of both directly vector-treated and not directly vector-treated tumors as well as pronounced infiltration of both tumor types with natural killer cells, macrophages, and T cells. T cells of these animals exhibited strong ex vivo cytotoxic activity against the tumor cells, indicating that the antineoplastic effect on untreated tumors was mediated by an antitumor immune response. Preexisting immunity against HSV-1 or measles virus had no detrimental effect on overall treatment efficacy. Our data indicate that MV-FMG expression in combination with viral oncolysis with or without clinically relevant chemotherapy for colon cancer treatment warrants further investigation.
Hoffmann
Dennis
D
Department of Molecular and Medical Virology, Institute of Microbiology and Hygiene, Ruhr-University Bochum, D-44801 Bochum, Germany.
Bayer
Wibke
W
Wildner
Oliver
O
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D019496:Cancer Vaccines / Q000235:genetics / Q000627:therapeutic use; D002459:Cell Fusion; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D000077146:Irinotecan; D008459:Measles virus / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050130:Oncolytic Virotherapy / Q000379:methods*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014760:Viral Fusion Proteins / Q000235:genetics*
D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D014760:Viral Fusion Proteins; D000077146:Irinotecan; D002166:Camptothecin