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 Newk’s Cares, and Ovarian Cycle, Jackson, Mississippi.
Michael Goldberg, PhD, is an Assistant Professor in the Department of Cancer Immunology & Virology at Dana-Farber Cancer Institute. Dr. Goldberg graduated Summa Cum Laude with an Hon. B.Sc. in Biological Chemistry from the University of Toronto. He subsequently received an M.Phil. in BioScience Enterprise from the University of Cambridge. Dr. Goldberg completed his Ph.D. in Biological Chemistry under the supervision of Institute Professor Robert Langer at the Massachusetts Institute of Technology (MIT), where he was a member of the founding class of the Harvard-MIT Division of Health Sciences and Technology’s Graduate Education in Medical Sciences program. Having focused on improving the efficiency of siRNA delivery during his doctoral research, he pursued post-doctoral training in the laboratory of Institute Professor Phillip Sharp in the Koch Institute for Integrative Cancer Research at MIT, where he worked to develop cancer-specific RNAi therapeutics. His research has been published in leading journals, including Nature and Nature Biotechnology. He has been fortunate to win several awards but counts the Liz Tilberis Award as one of his most revered. His current research interests include cancer immunotherapy and the creation of innovative platforms for drug delivery by combining the tools of chemistry, engineering, immunology, molecular biology, and nanotechnology. He is extremely grateful for the generous support of the OCRA, which is enabling his group to investigate the impact of standard-of-care chemotherapy on immune cells in the ovarian tumor microenvironment to enable mechanistic determination of a complementary immunotherapy. It is hoped that invoking the immune system could generate a memory response that might improve the magnitude and frequency of responses, leading to more durable outcomes.