Specific Genetic Mutations Impact Chemotherapy Resistance and Therapeutic Efficacy of Oncolytic Viruses in Ovarian Cancer.

Abstract

Epithelial Ovarian Cancer (EOC) is the most lethal gynecologic cancer and those affected are in urgent need of new therapeutic strategies. Standard treatment is surgery followed by taxane- and platinum-based chemotherapy, but the rate of relapse is high and the 5-year survival is only 45%. Oncolytic viruses (OV) are a promising approach to EOC therapy through remodeling the immune composition of the tumor microenvironment (TME). Treatment response in EOC tumors can differ based on the presence of key tumorigenic mutations. This study evaluated the impact of specific tumor mutations on the response to the current standard of care carboplatin, two promising OV candidates VSV∆M51 and MG1, an infected cell vaccine (ICV-MG1) regimen, and the anti-angiogenic drug Fc3TSR. Mice with tumors harboring constitutive K-Ras activation showed an enhanced response to carboplatin and VSV∆M51 treatment. Additionally, VSV∆M51 treatment prolonged survival of syngeneic mice bearing tumors with mutations in Pten and Kras, Pten and Trp53, or Trp53 and Brca2 with increased activation of CD4+ and CD8+ T lymphocytes in the peritoneal TME. To enhance OV potency, an MG1-based infected cell vaccine inducing expression of IL-21 or IL15+21 was developed and found to enable strong and long-lasting antitumoral immunity in two carboplatin refractory syngeneic models, ID8 Trp53-/- and STOSE. VSV∆M51 combined with the anti-angiogenic Fc3TSR enhanced efficacy in the ID8 model. In summary, OV-based immunotherapy has shown promise in diverse murine models of EOC-bearing clinically relevant mutations, thus laying the foundation for developing new OV-based strategies to target a large spectrum of EOC genotypes.