Ovarian cancer is the leading cause of death among gynecologic malignancies, and dramatic improvements in overall survival remaining wanting. Clinical data reveal that arousal of a patient’s own immune system can produce durable benefit in the context of numerous cancers. Unlike traditional cancer therapies, the immune system is adaptive and has capacity for memory. Adaptation is critical because cytotoxic agents select for resistant cancer clones, as tumors are heterogeneous and evolving. Memory is vital to achieving durable responses by preventing the recurrence that claims so many lives. Cancer immunotherapy generates a coordinated and proliferative response that is relevant across cancer subtypes and their underlying mutations. While immunotherapy may enable oncologists to consider a path from treatment towards cure, the fraction of patients who benefit from this modality remains low.
To increase the proportion of ovarian cancer patients who respond to immunotherapy, we seek to define an immunomodulatory agent that is complementary to standard-of-care chemotherapy. Rather than attempt to replace the standard-of-care, which is the backbone of therapy provided by most community oncologists, we have sought to leverage it. Specifically, we seek to understand the impact that chemotherapy has on the immune cells that are situated in and around ovarian tumors. Our initial studies in mice that have advanced disease have revealed that chemotherapy not only kills cancer cells but also increases the expression of an inhibitory receptor on cancer-killing immune cells. We are working to validate this finding in samples derived from patients by comparing their tissues before and after they received chemotherapy. This grant renewal will allow us to test our hypothesis that administering an antibody that blocks the inhibitory receptor will enable the immune system to combat the cancer more effectively following chemotherapy. Whereas chemotherapy alone selects for drug-resistant cells, leading to relapse, invoking the immune system produces a dynamic response to the dynamic disease.
Because our approach is based on an improved mechanistic understanding of chemotherapy’s role on the immune system rather than trial and error, we expect that neutralization of this immunotherapy target will improve the frequency and magnitude of responses relative to the immunotherapy that has been previously tested in ovarian cancer patients. We further intend to define surrogate biomarkers of efficacy, which would be useful upon clinical translation by enabling physicians to monitor whether the immune system has become activated robustly following treatment. We are hopeful that our preclinical data will lead to registration of a clinical trial that incorporates appropriate immunotherapy into standard-of-care practice, with a view toward generating curative outcomes.
This research has been generously supported by Ovarian Cycle, Jackson, Mississippi.