667. Natural Selection of a Neurovirulent Herpes Simplex Virus Type1 Strain via Passage in Human Glioma Xenografts

Abstract

The strategy of using oncolytic viruses (OVs) in cancer therapy is based on their replicative selectivity in tumor compared to normal tissue. In general, these tumor-tropic OVs are genetically engineered to be attenuated to minimize toxicity and for retargeting towards tumors. Directed genetic manipulation of viruses depends on knowledge of the host-virus interactions at the molecular level, which can be highly complex and context-dependent. Another approach is to utilize natural selection and evolution to adapt a virus to be more selective for tumor cells. We thus obtained a wild-type HSV1 strain harvested from a human patient with HSV1 encephalitis patient. This HSV1 was repeatedly passaged in nude mice with human glioblastoma xenografts. After 10 rounds of serial passage, we propagated and purified the passaged virus for subsequent experiments. To assay for phenotypic differences, the parent virus and passaged virus were compared in their replicative efficiency in glioma cells in vitro and in vivo, as well as in toxicity by injection in nude mouse brains. There was a statistical significant increase in the replication yield of the passaged virus compared to the parental virus. Although there was also a trend for enhanced anticancer efficacy of the paasaged virus compared to the parental virus, it did not reach a p value less than 0.05. There was no difference in the toxicity of either virus in nude mouse brains. These results suggest that natural evolution by serial passage may lead to a more efficacious oncolytic HSV1, but that more passages may be required to further evolve this strain.