James J. Petrik

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.

The Complex Tumor Microenvironment in Ovarian Cancer: Therapeutic Challenges and Opportunities

The tumor microenvironment (TME) in ovarian cancer (OC) has much greater complexity than previously understood. In response to aggressive pro-angiogenic stimulus, blood vessels form rapidly and are dysfunctional, resulting in poor perfusion, tissue hypoxia, and leakiness, which leads to increased interstitial fluid pressure (IFP). Decreased perfusion and high IFP significantly inhibit the uptake of therapies into the tumor. Within the TME, there are numerous inhibitor cells, such as myeloid-derived suppressor cells (MDSCs), tumor association macrophages (TAMs), regulatory T cells (Tregs), and cancer-associated fibroblasts (CAFs) that secrete high numbers of immunosuppressive cytokines. This immunosuppressive environment is thought to contribute to the lack of success of immunotherapies such as immune checkpoint inhibitor (ICI) treatment. This review discusses the components of the TME in OC, how these characteristics impede therapeutic efficacy, and some strategies to alleviate this inhibition.