Martin Cannon, PhD
2021 Collaborative Research Development Grant
University of Arkansas for Medical Sciences
Understanding and Targeting Myeloid Populations in Ovarian Cancer
Project Summary
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.
Bio
Martin J Cannon, PhD, is Professor of Microbiology and Immunology at the University of Arkansas for Medical Sciences (UAMS). He received his PhD in immunology from the University of London, and pursued postdoctoral research at the National Institute for Medical Research, London, and the Scripps Research Institute, La Jolla before moving to UAMS. Dr. Cannon’s research focuses on novel strategies for dendritic cell (DC) vaccination against ovarian cancer, including recent clinical studies on maintenance Th17-inducing DC vaccination, conducted in partnership with the Mayo Clinic SPORE for ovarian cancer. This timely award from the OCRA will support the development of an integrated and multi-faceted program to target myeloid cell-mediated immune suppression in the ovarian tumor microenvironment, with the goal of enhancing responses to immunotherapy, including DC vaccination. Dr. Cannon has published extensively in the field of ovarian cancer research, and his work has been supported by the Department of Defense Ovarian Cancer Research Program, the Rivkin Center and the National Institutes of Health. Dr. Cannon is a current member of the NIH Immuno-Oncology Research Special Emphasis Panel, and has served as Chair for DOD review panels in breast, prostate and ovarian cancer.