Ovarian tumors contain abundant numbers of infiltrating immune cells that can have a profound influence on the progression of disease and the response to various types of treatment. In particular, there is increasing recognition that tumor-associated macrophages (TAM) play a pivotal role in orchestrating the repertoire of defense mechanisms with ovarian tumors. TAM can strongly suppress anti-tumor immunity and responses to immunotherapy. TAM also promote metastatic spread of disease, angiogenesis (the formation of new blood vessels to support tumor growth) and resistance to chemotherapy. Not surprisingly, TAM infiltration in ovarian cancer has been associated increased patient morbidity and mortality.
This Collaborative Research Development Grant will explore independent but complementary approaches to inhibition of ovarian TAM in combination with clinically applicable treatments for ovarian cancer. Each project takes an experimental approach that has strong translational potential for advancement to clinical trials. Project 1 combines a dendritic cell (DC) vaccine that has shown promise of clinical benefit in a recently published Phase I trial in patients with stage IIIc/IV ovarian cancer with novel CD206-binding ovarian TAM-targeted peptides that alleviate immune suppression and boost the efficacy of DC vaccination in vivo. Project 2 applies innovative CAR-T technologies to targeted depletion of TAM combined with ovarian tumor-targeted mesothelin-specific CAR T cells that are the subject of ongoing clinical trials. CAR-T therapies are approved for treatment of leukemia, and are currently being extensively tested in clinical trials for other malignancies. Project 3 takes an orthogonal approach to ovarian cancer treatment by first identifying the biological roles of macrophages in the adaptive resistance to anti-VEGF therapy (which inhibits tumor angiogenesis), and then determining the in vivo efficacy of targeting TAM with specific antibody to bypass mechanisms of resistance to anti-VEGF treatment.
The primary purpose of the proposal is to test novel, complementary, and combinatorial strategies that i) gain insights into the role of TAMs in ovarian cancer resistance to treatment, and ii) incorporate TAM disruption as a cornerstone of therapy. The goal of these studies is to acquire preclinical results that support the overall goal of advancing one or more TAM-targeted treatments to early phase clinical trials in patients with recurrent ovarian cancer.