Efficacy of a Third-Generation Oncolytic Herpes Virus G47Δ in Advanced Stage Models of Human Gastric Cancer

Abstract

Advanced gastric cancer, especially scirrhous gastric cancer with peritoneal dissemination, remains refractory to conventional therapies. G47Δ, a third-generation oncolytic herpes simplex virus type 1, is an attractive novel therapeutic agent for solid cancer. In this study, we investigated the therapeutic potential of G47Δ for human gastric cancer. In vitro, G47Δ showed good cytopathic effects and replication capabilities in nine human gastric cancer cell lines tested. In vivo, intratumoral inoculations with G47Δ (2 × 105 or 1 × 106 plaque-forming units [PFU]) significantly inhibited the growth of subcutaneous tumors (MKN45, MKN74, and 44As3). To evaluate the efficacy of G47Δ for advanced-stage models of gastric cancer, we generated an orthotopic tumor model and peritoneal dissemination models of human scirrhous gastric cancer (MKN45-luc and 44As3Luc), which have features mimicking intractable scirrhous cancer patients. G47Δ (1 × 106 PFU) was constantly efficacious whether administered intratumorally or intraperitoneally in the clinically relevant models. Notably, G47Δ injected intraperitoneally readily distributed to, and selectively replicated in, disseminated tumors. Furthermore, flow cytometric analyses of tumor-infiltrating cells in subcutaneous tumors revealed that intratumoral G47Δ injections markedly decreased M2 macrophages while increasing M1 macrophages and natural killer (NK) cells. These findings indicate the usefulness of G47Δ for treating human gastric cancer, including scirrhous gastric cancer and the ones in advanced stages.