Alison O. Cudmore

Cancer genetics and response to oncolytic virus treatment for ovarian cancer

Ovarian cancers (OCs) are often defined as poorly immunogenic tumors that have low response rates to current immunotherapies and frequently develop resistance to chemotherapies. Oncolytic viruses (OVs) are an emerging therapeutic approach that is favored due to its multifactorial mechanism of action; OVs aim to enhance immune cell recovery and infiltration into the tumor, in addition to assisting the immune system to identify and target evasive tumors. While many different OVs have been studied, this review focuses on the four that have been extensively tested in preclinical models and clinical trials with OC patients: vaccinia viruses, vesicular stomatitis virus, herpes simplex 1, and adenoviruses. We will first explore how these viruses have been developed, modified and tested as monotherapies in OCs, with limited success. The various combinatorial approaches involving OVs that are currently being investigated to improve the outcomes for OC patients will then be addressed. Attention will be given to how the genetics of OC cells may influence response to OVs and how that has led to genetic modifications of OVs that improve the cancer specificity and efficacy of these therapies.

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. However, 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. 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 VSVΔM51 and MG1, an infected cell vaccine (ICV-MG1) regimen, and the antiangiogenic drug Fc3TSR. Mice with tumors harboring constitutive K-Ras activation showed an enhanced response to carboplatin and VSVΔM51 treatment. Additionally, VSVΔM51 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 tumor microenvironment. To enhance OV potency, an MG1-based infected cell vaccine inducing the expression of IL21 or IL15 + IL21 was developed and found to enable strong and long-lasting antitumoral immunity in two carboplatin-refractory syngeneic models, ID8-Trp53−/− and STOSE. VSVΔM51 combined with the antiangiogenic 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.