Improving Mucosal Melanoma Therapy by Harnessing the Immunogenicity of r3LCMV

Abstract/Summary Viral-based cancer therapies for cancer exert powerful antitumoral effects both through direct infection and lysis of tumor cells and by triggering immune responses against the tumor. Currently FDA approved oncolytic viruses are targeting melanoma and bladder cancer, and there is a growing list of viral agents on the horizon. However, current viral-based therapies have limitations in terms of their safety and efficacy, warranting development of novel agents. It has been suggested that an arenavirus like lymphocytic choriomeningitis virus (LCMV) could be attenuated to render it ideal for viral therapy against cancer. In this proposal, we demonstrate the powerful anti- tumor activity of a highly attenuated LCMV strain, r3LCMV. Engineered from LCMV, this virus is exceptionally immunogenic in mice and humans, and r3LCMV vectors expressing HPV antigens are already being clinically tested as a cancer vaccine. However, our data from multiple murine tumor models, including melanoma models, suggests that r3LCMV is exceptionally effective intratumorally (IT) even without expressing tumor antigens. Our group has been developing novel immunotherapies for melanoma with a focus on mucosal melanoma (MM), a particularly deadly melanoma variant of the mucosal surfaces. MM has one of the best immunocompetent models there is: the spontaneous oral MM tumors that occur naturally in pet (companion) dogs. This project will have 2 aims, each evaluating different aspect of this therapy and exploring different clinical settings: Aim 1: To determine whether neoadjuvant r3LCMV treatment improves disease-free survival (DFS) in dogs with naturally occurring MM. We will launch a placebo controlled veterinary trial to evaluate the effect of IT r3LCMV administration in the neoadjuvant setting for dogs diagnosed with MM. Aim 2: To utilize r3LCMV to improve cellular therapy of MM. TIL generated from canine MM tumors treated with r3LCMV or placebo will be compared for phenotype, ex-vivo function and clinical efficacy for the treatment of metastatic disease.