IL5 Receptor Therapy to Target MDSCs in Ovarian Cancer
Abstract
Despite current surgical and cytotoxic therapies, 80% of patients diagnosed with advanced epithelial ovarian cancer (EOC) develop recurrent disease, and only 30% of patients survive 5 years following diagnosis. There is an unmet need for effective therapies in the management and treatment of ovarian cancer. Our goal is to improve the overall survival of women suffering from this devastating disease. As an Early-Career Investigator in the Department of Defense Ovarian Cancer Academy, research in my laboratory is focused on identifying and developing therapeutic strategies for the treatment of advanced stage ovarian cancer. This pilot award is particularly exciting, given that it has the potential to rapidly provide a new immunotherapy for the treatment of ovarian cancer. One of the key hurdles for cancer treatment is the ability of tumor cells to evade the immune system, thereby preventing the body’s natural immune defenses from destroying them. A prominent mechanism of tumor immune evasion is the establishment of an environment that is immunosuppressive and prevents strong T cell-mediated antitumor responses. Myeloid-derived suppressor cells (MDSCs) are immune cells with potent immunosuppressive activity. They are enriched in tumors where they promote immunosuppression, tumor cell survival, angiogenesis, and metastasis. Therefore, the ability to eliminate MDSCs in the tumor microenvironment is an attractive therapeutic strategy for cancer. Unfortunately, we lack good markers and ways to target MDSCs in cancer. Our group recently identified the IL-5 receptor (IL-5Ra) as a cell surface protein that is highly expressed on the polymorphonuclear (PMN) set of MDSCs in both mouse and human cancers. This proposal seeks to explore the possibility of using antibodies that will bind to and deplete IL-5Ra MDSCs as a therapeutic strategy for ovarian cancer therapy. The goals of our research are to identify the mechanisms that drive IL-5Ra expression on PMN-MDSCs, determine the therapeutic efficacy of a murine version of the Food and Drug Administration (FDA)-approved IL-5Ra depleting antibody (benralizumab) alone and in combination with current immune checkpoint inhibitors in preclinical models of ovarian cancer, and characterize IL-5Ra expression on PMN-MDSCs in ovarian cancer patient tumor and blood. These preclinical studies have the potential to be rapidly translated in to clinical trials as benralizumab is already FDA-approved for the treatment of asthma. We hypothesize that the combination of IL-5Ra depletion with immune checkpoint inhibitors will be a safe and effective strategy to achieve durable responses in patients with advanced epithelial ovarian cancer. Our therapeutic approach is innovative and novel, as targeting the IL5 receptor has not been investigated as a cancer therapy. We anticipate that, if successful, our studies would support the design of a clinical trial combining benralizumab with a checkpoint inhibitor in patients with recurrent EOC, as the majority of clinical trials with checkpoint inhibitors are in patients with recurrent or platinum-resistant EOC. This research meets the specific needs outlined by the Department of Defense to improve the overall survival and quality of life for military Service members, their families, and other military beneficiaries that are either directly or indirectly affected by this devastating disease. It also aligns with their vision of eliminating ovarian cancer by providing preclinical evidence for a novel therapeutic agent with high potential efficacy in ovarian cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010192
Entities
People
- Erinn B. Rankin
Organizations
- Stanford University
- United States Army