Abstract IA19: Immunotherapy in ovarian cancer: Challenges and novel opportunities
Authors: Zamarin Dmitriy 
Published: September 2020

Abstract
Breakthroughs in tumor immunology have led to development of novel therapies targeting the mechanisms governing tumor resistance to the immune system, such as programmed death receptor -1 (PD-1) and its ligand PD-L1. Based on these findings, therapy with PD-1 and PD-L1 blocking antibodies has been evaluated in several trials in epithelial ovarian cancer. Unfortunately, to date these drugs have demonstrated rather limited single-agent activity, while predictors of response and resistance as well as general mechanisms of immune recognition in ovarian cancer remain poorly characterized. Ovarian cancer is clinically and biologically distinct from cancers such as lung cancer and melanoma, where immune checkpoint blockade has had more success. These differences bear direct impact on patients’ clinical experience, utility of known biomarkers, and rationale for specific therapeutic combinations. Below, we highlight some of the clinical and biologic features of epithelial ovarian cancer that present challenges for therapeutic implementation of immune checkpoint blockade and provide rationale for combination strategies that may help overcome some of the challenges. 1. Ovarian cancer patients frequently discontinue immune checkpoint blockade early due to symptomatic disease progression. Due to the unique pattern of metastatic disease, characterized by peritoneal carcinomatosis and/or ascites, ovarian cancer patients are uniquely vulnerable to symptomatic disease progression and may often be unable to tolerate early disease growth for the treatment duration required to allow time for immune response. We have identified several pretreatment clinical factors, including bulky peritoneal disease, liver metastases, and high neutrophil-to-lymphocyte ratio, to be associated with early discontinuation of therapy. Overall, it is likely that immune therapy should not be reserved as a late-line therapy for patients with refractory and bulky disease, but rather should be used earlier in patients with lower disease burden, allowing for the potential delayed benefit in the patients who can tolerate early tumor growth. 2. Combination therapies may extend the benefit of immune checkpoint blockade to a larger percentage of ovarian cancer patients. Several early studies have highlighted that combinations of PD-1/PD-L1 blockade with other agents may extend the benefit of immunotherapy to a larger percentage of ovarian cancer patients. These include combinations with chemotherapy, CTLA-4 blockade, and PARP inhibitors. However, even with these early signals of activity, biomarkers of response remain unknown. 3. Biomarkers predictive of response in other cancer types have poor predictive value in ovarian cancer. Studies in other cancers have identified the overall tumor mutational burden (TMB) and tumor PD-L1 expression to be predictive of response to immune checkpoint blockade. However, unlike melanoma and lung cancer, ovarian cancer is in general characterized by low TMB, and is driven by complex genetic alterations resulting in several prognostic mutational processes (e.g., HRD, fold-back inversions, and tandem duplications). Our analyses to date indicate that TMB is not predictive of response to immune checkpoint blockade. We also failed to find any association between the presence of deleterious germline or somatic BRCA mutations and response to immune checkpoint blockade. Lastly, reports from the largest studies of immune checkpoint blockade in ovarian cancer to date have failed to identify significant enrichment of responses in patients whose tumors exhibit positivity for PD-L1 expression. These findings once again highlight the ongoing unmet need to identify the mechanisms of response and resistance to immunotherapy and suggest that the unique biology of ovarian cancer may require testing of alternative hypotheses. 4. Tumor heterogeneity poses a challenge to development of valid biomarkers and effective immunotherapies in ovarian cancer. Epithelial ovarian cancer is subject to marked inter- and intratumoral heterogeneity with divergent tumor clonal composition in different intraperitoneal tumor sites, which has been demonstrated to be associated with marked heterogeneity in the tumor microenvironment. On the transcriptional level, even within the same patient, tumor cells isolated from multiple tumor sites exhibit marked tumor cell-intrinsic transcriptional heterogeneity, which is in turn associated with immune heterogeneity in the tumor microenvironment. This creates challenges to development of effective tissue-based biomarkers for cancer immunotherapy, as sampling of multiple tumor sites is logistically not feasible. Radiomics measures provide a potential noninvasive solution to measure tumor heterogeneity. Our recent findings indeed demonstrate that low intra- and intertumor heterogeneity are associated with durable clinical benefit from immunotherapy in ovarian cancer. 5. Novel combination strategies to overcome tumor heterogeneity may be required to make immune checkpoint blockade effective in all ovarian cancer patients. Tumor microenvironment heterogeneity thus presents a significant challenge for development of effective immunotherapies in ovarian cancer. To overcome the TME heterogeneity problem, successful immunotherapies in ovarian cancer will likely require combinations of agents that could drive T-cell infiltration into all tumors. To this end, we are exploring regional therapeutic approaches using oncolytic viruses. Using preclinical tumor models, we have demonstrated that intratumoral therapy with oncolytic viruses can drive infiltration of T cells into distant, noninfected tumors and potentiate responses to immune checkpoint blockade. Our studies have highlighted that mechanistically, intratumoral therapy with oncolytic virus acts as an “in situ” vaccine and induces/expands tumor-specific T cells that can carry out their activity on a systemic level. Based on these findings, we have initiated a trial of intraperitoneally administered oncolytic virus in combination with systemic PD-L1 blockade in patients with advanced ovarian cancer. In conclusion, single-agent immune checkpoint blockade in ovarian cancer to date has yielded poor efficacy results, while biomarkers of response are yet to be defined. Understanding of the relationship between ovarian cancer genetics, tumor heterogeneity, and anti-immune response will be key to development of novel biomarkers and therapeutic combinations.
Citation Format: Dmitriy Zamarin. Immunotherapy in ovarian cancer: Challenges and novel opportunities [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA19.