Degree
Doctor of Biomedical and Veterinary Medical Sciences-Pathobiological Sciences (PVMPB)
Department
Department of Pathobiological Sciences
Document Type
Dissertation
Abstract
Current cancer immunotherapies include immune checkpoint inhibitors, adoptive cellular therapy, and cancer vaccines. While some of these therapies have met with great clinical success, they are associated with several limitations. Oncolytic virotherapy (OVT) has emerged as a bonafide promising immunotherapy, that uses viral infection to liberate tumor antigens in an immunogenic context to promote the development of anti-tumor immune responses. At present, Talimogene laherparepvec (T-VEC; Imlygic™), a modified type 1 herpes simplex virus (HSV-1) is the only FDA approved OVT for human cancer treatment (melanoma). While T-VEC is associated with limited response rates, its modest efficacy supports the continued development of novel OVT viruses.
First, we investigated the efficacy of a the live-attenuated vaccine strain HSV-1(VC2), as an OVT in a syngeneic B16F10-derived mouse model of melanoma. VC2 possesses mutations in two of its viral envelope proteins: glycoprotein K and UL20, rendering the virus unable to enter into neurons via their axonal termini both in vitro and in vivo. Intratumoral treatment of mice engrafted with modified B16F10 melanoma cells with VC2, slowed tumor growth rates and significantly prolonged survival. VC2-treated mice that survived initial tumor engraftment were able to reject a second tumor engraftment challenge We found that VC2 treatment resulted in increased intratumoral T cell infiltration, and a decrease in immunosuppressive regulatory T cells.
We hypothesized that VC2 may be used to deliver tumor associated antigens to promote enhanced anti-tumor directed responses. We tested this hypothesis in mice using chicken ovalbumin (OVA) as a surrogate tumor-associated antigen in the B16cOVA melanoma models. VC2 was engineered to express a fragment of OVA fused to the viral VP26 capsid protein. Vaccination with VC2-OVA induced both an OVA-specific T cell responses. Intradermal vaccination with VC2-OVA conferred significant protection and prolonged the survival of mice which had been challenged with B16cOVA cells. Therapeutic treatment with VC2-OVA resulted in reduced lung colonization of tumor cells in mice challenged intravenously with B16cOVA cells. These findings confirm the remarkable efficacy, safety, and immunogenicity profiles of VC2. Importantly, these results demonstrate that VC2 holds promise for the delivery of heterologous antigens for personalized cancer immunotherapy.
Date
3-7-2022
Recommended Citation
Uche, Ifeanyi Kingsley, "The Herpes Simplex Virus Type-1 (HSV-1), VC2 Live-Attenuated Vaccine Strain Induces Robust Antitumor Immune Responses and Ameliorates Intra-Tumor Immunosuppression in an Immunocompetent B16f10-Derived Murine Melanoma Model" (2022). LSU Doctoral Dissertations. 5764.
https://repository.lsu.edu/gradschool_dissertations/5764
Committee Chair
Kousoulas, Konstantin Gus
DOI
10.31390/gradschool_dissertations.5764