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 antitumor immune responses. The only currently FDA-approved
oncolytic virotherapy,
T-Vec, is a modified type 1 herpes simplex virus (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 ability of the virus 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 nonhuman 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 regulatory T 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.