Novel Oncolytic Herpes Simplex Virus 1 VC2 Promotes Long-Lasting, Systemic Anti-melanoma Tumor Immune Responses and Increased Survival in an Immunocompetent B16F10-Derived Mouse Melanoma Model

Abstract

Oncolytic virotherapy (OVT) is now understood to be an immunotherapy that uses viral infection to liberate tumor antigens in an immunogenic context to promote the development of anti-tumor immune responses. The only currently FDA approved oncolytic virotherapy, T-Vec™, is a modified herpes simplex virus type I (HSV-1). While T-Vec™ is associated with limited response rates its modest efficacy supports the continued development of novel OVT viruses. Herein, we test the efficacy of a recombinant HSV-1, VC2, as an OVT in a syngeneic B16F10-derived mouse model of melanoma. VC2 possesses mutations that block its ability to enter neurons via axonal termini. This greatly enhances its safety profile by precluding the virus’s ability to establish latent infection. VC2 has been shown to be a safe, effective vaccine against both HSV-1 and HSV-2 infection in mice, guinea pigs, and non-human primates. We found that VC2 slows tumor growth rates and that VC2 treatment significantly enhances survival of tumor-engrafted, VC2-treated mice over control treatments. VC2-treated mice that survived initial tumor engraftment were resistant to a second engraftment as well as colonization of lungs by intravenous introduction of tumor cells. We found that VC2 treatment induced substantial increases in intratumoral T-cells and a decrease in immunosuppressive T-regulatory cells. This immunity was critically dependent on CD8+ T-cells and less dependent on CD4+ T-cells. Our data provide significant support for the continued development of VC2 as an OVT for the treatment of human and animal cancers. Importance Current oncolytic virotherapies possess limited response rates. However, when certain patient selection criteria are used, oncolytic virotherapy response rates have been shown to increase. This, in addition to the increased response rates of oncolytic virotherapy in combination with other immunotherapies, suggests that oncolytic viruses possess significant therapeutic potential for the treatment of cancer. As such, it is important to continue to develop novel oncolytic viruses as well as support basic research into their mechanisms of efficacy. Our data demonstrate significant clinical potential for VC2, a novel Type 1 oncolytic herpes simplex virus. Additionally, due to the high rates of survival and the dependence on CD8+ T-cells for efficacy, our model will enable study of the immunological correlates of protection for VC2 oncolytic virotherapy and oncolytic virotherapy in general. Understanding the mechanisms of efficacious oncolytic virotherapy will inform the rational design of improved oncolytic virotherapies.

The Effect of Herpes Simplex Virus-Type-1 (HSV-1) Oncolytic Immunotherapy on the Tumor Microenvironment

“…Our laboratory has recently identified mutations that blocks HSV-1 entry into neurons [ 110 ]. This novel oHSV, VC2, replicates to similar viral titers to its parental HSV-1 F strain virus, but is not neuroinvasive, and in a B16F10-derived mouse melanoma model, demonstrated significant efficacy and altered the immunosuppressive TME [ 25 ].…”

“…However, for HSV-1 OVs, pre-existing immunity is a concern as the virus may be rapidly cleared by pre-existing circulating neutralizing antibodies before it reaches its target tissues. Studies from our laboratory and other groups have demonstrated that prior immunity to HSV-1 does not have an effect on the efficacy of HSV-1 OVT in mice [ 16 , 25 ] or humans [ 15 ], although others have reported that it did enhanced therapeutic outcome in vivo [ 48 ]. It has been suggested that the latter may be true, particularly for herpesviruses, which as part of their replication strategy periodically reactivate and spread, causing continued activation of robust adaptive immune responses [ 113 ].…”

“…A number of candidate oHSVs are currently in development [ 24 ]. Our group and others have demonstrated the significant impact of oHSV OVT on the development of anti-tumor immune responses in pre-clinical or clinical studies [ 25 , 26 , 27 , 28 ]. Specifically, these studies have highlighted the ability of oHSVs to change the TME from “cold” or immunosuppressive to “hot” or immunostimulatory as a component of their efficacy.…”

“…Given the central role of the TME in controlling the development of anti-tumor immune responses, understanding the cellular and molecular changes in the TME during OVT would inform the development of more efficacious immunotherapies for the treatment of human and animal cancers. While the pre-clinical pipeline of oHSV is rich with promising candidates [ 25 , 26 , 27 , 28 , 29 ], we focus in this section on several oHSVs for which there is clinical data.…”

“…GM-CSF functions as a potent immune stimulator by promoting the recruitment and maturation of DCs and macrophages [ 16 ]. It is not clear what contribution the GM-CSF makes to anti-tumor efficacy of T-VEC™ as other vectors have shown efficacy in the absence of cytokine transgenes [ 25 ].…”