Multi-attenuated herpes simplex virus-1 mutant G207 exerts cytotoxicity against epithelial ovarian cancer but not normal mesothelium and is suitable for intraperitoneal oncolytic therapy

Recombinant strains of herpes simplex virus-1 (HSV-1) harboring mutations i n the infected cell product (ICP)34.5 region lose their neurovirulence and replicate more efficiently in dividing tumor cells than stationary cells, b ecoming replication-selective oncolytic agents. Additional mutation of the ICP6 gene, which encodes ribonucleotide reductase, further impairs the abil ity of HSV-1 mutants to replicate in normal cells, enhancing tumor selectiv ity. The present study investigated the effect of HSV-G207, a recombinant H SV-1 lacking ICP34.5 and ICP6, against epithelial ovarian cancer (EOC) in v itro and in vivo in a mouse xenograft model. To assess the selectivity of m ultimutated HSV-G207 against malignant cells, HSV-G207 and wild-type HSV-F were comparatively tested against normal human peritoneal mesothelial cells and EOC cells in vitro. HSV-G207 infected both EOC cells and mesothelial c ells; however, unlike EOC cells, mesothelial cells provided a poor substrat e for replication of HSV-G207. In contrast to wild-type HSV-F, HSV-G207 exe rted a potent oncolytic effect on EOC cells but spared normal mesothelial c ells in vitro. Primary EOC cells were more sensitive to the virus than esta blished EOC cell lines. A single intraperitoneal injection of HSV-G207 resu lted in a significant reduction in tumor volume and tumor spread in vivo. H SV-G207 was shown to penetrate deeply within tumor nodules and caused no ap parent intraperitoneal toxicity. Oncolytic therapy with multimutated replic ation-restricted HSV may offer a novel approach in the treatment of EOC.