The role of ICPO-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 ICPO null mutants has not been described. This study characterizes a novel second-generation oncolytic herpes simplex type 1 vector null for the ICPO 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 ICPO's function in interferon signaling pathways and the observed oncolytic capacity of ICPO mutants. Using an immunocompetent murine model of breast adenocarcinoma we demonstrate that the ICPO mutant KM100 completely eradicates tumors in similar to 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.