Oncolytic viral therapy for disseminated peritoneal ovarian cancer using a novel replication-competent herpes simplex virus type 1 mutant in mice.

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We prepared two attenuated mutant HSV-1 strains. One is an HSV-1 mutant, hrR3, and another is a new replication competent HSV-1 mutant, HR522 ; this virus, expressing the lacZ reporter gene, induces syncytium formation in infected cells. We compared the efficacy of HR522 with Taxol and hrR3 in the treatment of nude mice harboring human ovarian cancer cells. We also examined the effect of the prodrug ganciclovir (GCV) on the treatment mediated by these HSVs. The survival of mice treated with a high titer hrR3 (5x10^7 plaque-forming units ; PFU) was significantly prolonged as compared to the group given Taxol (p<0.0001 ; Log-Rank test). Although the survival of mice treated with high titer HR522 (5x10^7 PFU) was not significantly prolonged compared with Taxol-treated group (p=0.212 ; Log-Rank test), GCV markedly enhanced the efficacy of HR522 administration (p<0.005 ; vs Taxol ; Log-Rank test). The lacZ gene product, visualized using 5-brorno-4-chrolo-3-indoryl-β-D- galactopyranoside (X-gal) histochemistry, was detected in HR522-treated tumors in areas also exhibiting apoptotic changes. Another study demonstrated that a clonal derivative of HSV-1 strain HF done 10 very effectively treated peritoneally disseminated neoplasm in an immunocompetent animal model and that all of survived mice acquired resistance to rechallenge of tumor cells. HF clone 10 induces syncytia formation in vitro. A sequential administration ofHF clone 10 attained a long-term survival over 90 days after tumor injection in 8 of the 9 treated mice without any signs of diseases. The results suggested that treatment of peritoneally disseminated tumor with HF clone 10 induced a specific anti-tumor immune response. We found that clone 10 has a deletion of 39kbp in the right end of UL and UL/IRL junction, resulting in the loss of UL 56 expression. Moreover, a 23kbp deletion and extensive rearrangement were observed in the left end of the genome.