Degree

Doctor of Philosophy (PhD)

Department

Pathobiological Sciences

Document Type

Dissertation

Abstract

Melanoma accounts for 90% of skin cancer-related deaths in humans. Treatment options for metastatic melanoma in people is very limited. Melanoma is considered to be an immunogenic tumor, spurring interest in development of immunotherapies for the treatment of metastatic melanoma. Oncolytic virotherapy has been widely investigated. The first ever oncolytic virotherapy to receive FDA-approval is an HSV-1-based virus (Talimogene Laherperavec (T-Vec) or Imlygic) containing a transgene for human GM-CSF to enhance anti-tumor immune responses after injection. Durable response rate in human patients was only 16% despite impressive efficacy in anti-tumor effects in vitro and in murine tumor models. Novel viruses with enhanced immune-stimulating properties and improved efficacy and safety profiles are needed. Further, the lack of concordance of preclinical murine studies with results in human clinical trials highlights the need for improved murine tumor modeling strategies.

Our laboratory developed the live-attenuated HSV-1 (VC2) vaccine strain, which has shown efficacy in protection against lethal intravaginal HSV-1 and HSV-2 challenge after a single intramuscular injection in mice. VC2 replicate efficiently in permissible cells but does not enter ganglionic axons. Further, VC2 is highly immunogenic generating strong cell-mediated and humoral immune responses. We developed an immunocompetent double-labeled murine melanoma model for testing the immune-modulating and adjuvant effects of oncolytic herpesviruses. Intratumoral virotherapy using VC2 resulted in significant increases in CD3+ T cells and IBA-1+ macrophages in the tumor microenvironment, but reduced expression of arginase-1, a marker of the M2, pro-tumorigenic macrophage phenotype. Median survival times (MST) of VC2 treated mice were nearly twice that of mock-treated controls. We also found that bioluminescence allows for more sensitive assessment of anti-tumor responses during the acute inflammatory phase of treatment during which pseudoprogression can result in misleading increases in tumor volumes using traditional caliper measurements. Our findings suggest that the remarkable immunogenicity of VC2 makes it a good candidate as a vector for tumor vaccine development and our model allows for sensitive assessment of response to therapy in the face of marked acute inflammation. These findings represent significant progress in viral vector development for cancer therapy and in modeling strategies for testing immune-stimulating anti-cancer therapies.

Date

7-3-2018

Committee Chair

Kousoulas, Konstantin Gus

Available for download on Wednesday, July 03, 2019

Share

COinS