Replication-selective herpes simplex virus type 1 mutant therapy of cervical cancer is enhanced by low-dose radiation

Herpes simplex virus type 1 (HSV- 1)- based oncolytic treatment is a promising therapeutic approach for malignancy. Recombinant strains of HSV- 1 containing mutations in the ICP 34.5 protein have been shown to replicate preferentially in rapidly proliferating malignant cells, resulting in a direct cytolytic effect. We assessed the efficacy of multimutated HSV- 1 strains on human cervical cancer, and then used these viruses in combination with radiation therapy, the standard treatment for cervical cancer. The HSV- 1 mutants 4009, 7020, 3616, and G207 induced significant lysis of three established human cervical cancer cell lines in vitro in a dose- dependent manner. G207 intratumoral treatment of established subcutaneous C33a tumors in severe combined immunodeficient (SCID) mice significantly reduced tumor burden by 50%. Weekly and triweekly treatments improved efficacy and inhibited flank tumor growth in an administration frequency- dependent manner without toxicity. Combination therapy of a low dose of radiation (1.5 or 3 Gy) and replication- selective HSV mutants infection exhibited increased antitumor effects against cervical cancer cells in vitro. The in vivo effect of G207 combined with low- dose radiation was studied in Me180 xenografts in athymic mice. Treatment of established Me180 tumor nodules with 3 Gy followed by intratumoral G207 administration greatly improved efficacy, resulting in 42% complete eradication of tumor. In conclusion, single and multiple intratumoral injections of G207 significantly reduced tumor burden in xenogeneic models of cervical cancer, and the addition of low- dose radiation further potentiated the effect. These results suggest that replication- selective HSV- 1 mutants may be potent oncolytic agents for the treatment of cervical cancer.