The role of ICP0-Null HSV-1 and interferon signaling defects in the effective treatment of breast adenocarcinoma.
Oncolytic viruses that selectively replicate in cancer cells have been described for over 50 years. Despite the observation by several groups that multimutated herpes simplex type 1 vectors are oncolytic in a variety of murine tumor models, the oncolytic potential of ICP0 null mutants has not been described. This study characterizes a novel second-generation oncolytic herpes simplex type 1 vector null for the ICP0 gene. We tested three mutant viruses and found that all were selectively cytotoxic in a variety of human and murine tumor cells in vitro. Furthermore, we provide evidence of a mechanistic link between ICP0's function in interferon signaling pathways and the observed oncolytic capacity of ICP0 mutants. Using an immunocompetent murine model of breast adenocarcinoma we demonstrate that the ICP0 mutant KM100 completely eradicates tumors in approximately 80% of treated animals and significantly increases survival. Our data suggest that active viral replication is necessary for effective tumor regression. In addition, we characterized the potential of KM100 as an anti-tumor vaccine since cured mice were found to elicit a robust anti-tumor immune response and were refractory to subsequent tumor growth upon rechallenge.
Hummel
Jeff L
JL
Institute for Molecular Medicine and Health, Centre for Gene Therapeutics, Department of Pathology and Molecular Medicine, McMaster University, MDCL 5026, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5.
Safroneeva
Ekaterina
E
Mossman
Karen L
KL
D000230:Adenocarcinoma / Q000473:pathology* / Q000628:therapy; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology* / Q000628:therapy; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D018259:Herpesvirus 1, Human / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics*; D007372:Interferons / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000628:therapy; D050504:Oncolytic Viruses / Q000235:genetics; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
D017874:Immediate-Early Proteins; D007372:Interferons; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1