664. Therapeutic Effect of Oncolytic Herpes Simplex Virus Type 1 (G47Δ) in Combination with Chemotherapy on Colorectal Cancer

Abstract

One of the reasons for the difficulty of curing unresectable advanced stage colorectal cancer is that cancer cells acquire resistance to anticancer drugs. Oncolytic virus therapy is a potent candidate for developing a new therapeutic approach that counteracts drug resistance, in which an oncolytic virus kills cancer cells in the course of tumor cell specific viral replication. G47Δ is a third-generation oncolytic herpes simplex virus type 1 with triple mutations in the γ34.5, ICP6, and α47 genes. G47Δ not only destroys cancer cells directly, but also induces systemic antitumor immunity efficiently. In the present study, we investigate the efficacy of G47Δ in combination with 5-fluorouracil (5-FU) or oxaliplatin for colorectal cancer. A human colorectal cancer cell line HCT116 and a murine colorectal cancer cell line CT26 were used in vitro to examine cytotopathic effects and replication capabilities of G47Δ. Combination index analyses demonstrated additive or synergistic effects of G47Δ when used in combination with chemotherapeutic drugs. Importantly, cytotoxic anticancer drugs did not affect the replication capability of G47Δ in vitro. In vivo experiments were performed using BALB/c mice bearing syngeneic subcutaneous CT26 tumors or athymic mice bearing subcutaneous HCT116 tumors. Each established tumor was treated with 2-time intratumoral injections with G47Δ (1×106 pfu) or mock, with concomitant intraperitoneal injections with chemotherapeutic drugs (3mg/kg 5-FU three times or 5mg/kg oxaliplatin four times) or vehicle. Combination therapy inhibited tumor growth significantly better than each therapy alone. Next, we established a 5-FU-resistant CT26 cell line (CT26FuR) by continuously exposing the naive CT26 cells to increasing concentrations of 5-FU. The tolerability of the CT26FuR against 5-FU was confirmed in vitro and in vivo. Cytotopathic effect and replication capability of G47Δ in CT26FuR cells were comparable to those in naive CT26 cells in vitro. Also in vivo, intratumoral administration of G47Δ was as efficacious in subcutaneous CT26FuR tumors as in CT26 tumors. In conclusion, G47Δ was shown efficacious for colorectal cancer both in vitro and in vivo. G47Δ may be especially useful for the treatment of multi-drug resistant colorectal cancer.