Third‐generation oncolytic herpes simplex virus inhibits the growth of liver tumors in mice

Abstract

Multimodality therapies are used to manage patients with hepatocellular carcinoma (HCC), although advanced HCC is incurable. Oncolytic virus therapy is probably the next major breakthrough in cancer treatment. The third‐generation oncolytic herpes simplex virus type 1 (HSV‐1) T‐01 kills tumor cells without damaging the surrounding normal tissues. Here we investigated the antitumor effects of T‐01 on HCC and the host's immune response to HCC cells. The cytopathic activities of T‐01 were tested in 14 human and 1 murine hepatoma cell line in vitro. In various mouse xenograft models, HuH‐7, KYN‐2, PLC/PRF/5 and HepG2 human cells and Hepa1‐6 murine cells were used to investigate the in vivo efficacy of T‐01. T‐01 was cytotoxic to 13 cell lines (in vitro). In mouse xenograft models of subcutaneous, orthotopic and peritoneal tumor metastasis in athymic mice (BALB/c nu/nu), the growth of tumors formed by the human HCC cell lines and hepatoblastoma cell line was inhibited by T‐01 compared with that of mock‐inoculated tumors. In a bilateral Hepa1‐6 subcutaneous tumor model in C57BL/6 mice, the growth of tumors inoculated with T‐01 was inhibited, as was the case for contralateral tumors. T‐01 also significantly reduced tumor growth. T‐01 infection significantly enhanced antitumor efficacy via T cell‐mediated immune responses. Results demonstrate that a third‐generation oncolytic HSV‐1 may serve as a novel treatment for patients with HCC.

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].…”

Translational Considerations to Improve Response and Overcome Therapy Resistance in Immunotherapy for Hepatocellular Carcinoma

“…Therefore, development of new preclinical models to evaluate the effects of oncolytic viruses in HCC will pave the road for advanced clinical trials and speed up development of new cancer treatments. In line with that, new generations of OVs have been developed with greater potential to specifically target tumor cells and stimulate the immune response [ 163 , 164 ]. Recently, Nakatake et al [ 163 ] examined the antitumor activities and immune response of third-generation HSV T-01 in HCC cell lines and mouse xenograft models.…”

“…In line with that, new generations of OVs have been developed with greater potential to specifically target tumor cells and stimulate the immune response [ 163 , 164 ]. Recently, Nakatake et al [ 163 ] examined the antitumor activities and immune response of third-generation HSV T-01 in HCC cell lines and mouse xenograft models. Application of the virus successfully led to increased expression of MHC class I molecules on tumor cells, which further stimulated CD8 + T cell-mediated immune response.…”

Neoadjuvant Use of Oncolytic Herpes Virus G47Δ Enhances the Antitumor Efficacy of Radiofrequency Ablation

“… 8 Oncolytic HSV-1 has shown efficacy for HCC in preclinical studies. 9 , 10 Thus, oncolytic viruses, including G47Δ, seem promising for a variety of cancers, although they are yet to be developed for HCC.…”