Complementing standard-of-care treatment with empirically determined combination immunotherapy to improve overall survival in ovarian cancer
Michael S. Goldberg1, Christina A. Hartl1
1Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA
With survival rates among ovarian cancer patients increasing only marginally in the last 40 years, there is an urgent need to develop novel strategies for improving outcomes. We propose to combine standard-of-care chemotherapy with an empirically determined immunotherapy to improve responses in mice and, ultimately patients. Using the ID8-Vegf murine model of ovarian cancer, we investigated the effect of carboplatin/paclitaxel chemotherapy on the immune compartment among tumor-bearing mice. Surprisingly, gene expression analysis revealed that common markers of immunosuppression, such as PD-1, were scarcely upregulated. Instead, we observe a significant increase in the expression of factors associated with myeloid populations, including ARG1. To interrogate these findings, we performed flow cytometry, which confirmed the expression of these targets at the protein level.
In order to ensure that we focus on clinically relevant targets, we also analyzed human ovarian cancer samples for changes in immune cell markers following chemotherapy. In agreement with the murine data, a striking up-regulation of ARG1 and other markers of myeloid cells was observed. Moving forward, we will inhibit ARG1 following chemotherapy in tumor-bearing mice and then assess for synergy by monitoring overall survival. Finally, we seek to define the mechanism of cooperativity between these complementary therapies and reveal potential surrogate biomarkers that correlate with survival.
We believe that these are the first data describing the effects of chemotherapy on tumor-associated immune cells both from mice and patients. Understanding how standard-of-care therapy modifies the tumor microenvironment can reveal rational complementary immunotherapy targets. We are hopeful that these proof-of-concept studies will lay the foundation for clinical trials that dramatically impact the survival of ovarian cancer patients.