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. G47D, 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 G47D for human gastric cancer. In vitro, G47D showed good cytopathic effects and replication capabilities in nine human gastric cancer cell lines tested. In vivo, intratumoral inoculations with G47D (2 Â 10 5 or 1 Â 10 6 plaqueforming units [PFU]) significantly inhibited the growth of subcutaneous tumors (MKN45, MKN74, and 44As3). To evaluate the efficacy of G47D 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. G47D (1 Â 10 6 PFU) was constantly efficacious whether administered intratumorally or intraperitoneally in the clinically relevant models. Notably, G47D 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 G47D injections markedly decreased M2 macrophages while increasing M1 macrophages and natural killer (NK) cells. These findings indicate the usefulness of G47D for treating human gastric cancer, including scirrhous gastric cancer and the ones in advanced stages.

Oncolytic virotherapy with SOCS3 enhances viral replicative potency and oncolysis for gastric cancer

“…Moreover, enrollment of the subsequent phase II clinical trial (UMIN000015995) has also just finished and come out expected results. Our collaborators have also recently reported the preclinical therapeutic evaluation by G47Δ intratumoral administration in an orthotopic gastric cancer model, which mimics the clinical presentation of refractory scirrhous gastric cancer [ 28 ]. In the current study, we generated a newly designed oHSV expressing SOCS3 that has the same genetic backbone of G47Δ.…”

Herpes Simplex Virus Oncolytic Immunovirotherapy: The Blossoming Branch of Multimodal Therapy

“…Second, ICP47 is an immune evasion protein blocking antigen presentation in infected cells: thus, tumor cells infected with a ∆US12 virus expose more efficiently viral and tumor antigens on the plasma membrane and are more immunostimulatory than cells infected with a wild type (wt) virus. These astounding combined properties, deriving from the deletion of a single gene, were widely exploited for the educated construction of triply-mutated oHSVs, like oHSV G47∆ and oHSV T-01 [25,46,[52][53][54]. Notably, US11 expression by G47∆ recombinant rescued viral replication in glioblastoma stem-like cells (GSCs, more related to neural stem cells, NSCs), where replication of ∆γ 1 34.5 recombinants, like G207, was restricted [55,56].…”

The Double-Edged Sword Role of Viruses in Gastric Cancer

“…Moreover, preclinical trials have been conducted with the use of third generation oncolytic HSV-1–G47∆, which is a triple mutated virus developed by adding another deletion mutation to the genome of a second-generation HSV-1—G207 [ 181 ]. The use of this virus in GC (gastric cancer) decreased the level of M2 macrophages and increased the level of M1 macrophages and NK cells [ 181 ].…”

“…Moreover, preclinical trials have been conducted with the use of third generation oncolytic HSV-1–G47∆, which is a triple mutated virus developed by adding another deletion mutation to the genome of a second-generation HSV-1—G207 [ 181 ]. The use of this virus in GC (gastric cancer) decreased the level of M2 macrophages and increased the level of M1 macrophages and NK cells [ 181 ]. Interestingly, a strong antiviral response was reported leading to a controversial conclusion that innate immunity stimulated by oncolytic virus treatment may facilitate the priming of antitumor immunity [ 181 ].…”

“…The use of this virus in GC (gastric cancer) decreased the level of M2 macrophages and increased the level of M1 macrophages and NK cells [ 181 ]. Interestingly, a strong antiviral response was reported leading to a controversial conclusion that innate immunity stimulated by oncolytic virus treatment may facilitate the priming of antitumor immunity [ 181 ].…”