The areas of focus and expertise of Peter A. Cohen, M.D., include the biology and activation of dendritic cells in both vaccine and immunoadjunct therapeutics; myeloid-derived suppressor cells (MDSCs); T cell adoptive therapy with emphasis on the critical role of CD4+ effector T cells; and immunopotentiation by chemotherapeutic agents and small molecules.
Dr. Cohen's research team has refined methods to drive effector T cell cultures by the use of optimally activated, antigen-pulsed dendritic cells, which are applicable both to mouse tumor models and to clinical trials.
The team has also identified, however, that myeloid cells in general — including both dendritic cells and MDSCs — are susceptible to distinctive, differentiative programming. The team has found that dominant pathway programming depends on what compartment the myeloid cell is in and which ambient cytokines are in play.
The ability to emulate these compartmental controls of dendritic cell function, including homeostatic proliferation, has enabled the research team to identify optimal culture properties for robust propagation of specific T cells, in both mouse and human settings.
This has led to the launching of a new cell culture system that for the first time facilitates the rapid outgrowth of both CD4+ and CD8+ T cells that can attack cancer cells expressing common antigens such as MUC1 and HER2/neu. Because the vast majority of human cancers express either MUC1 or HER2, a clinical trial is currently being crafted to reinfuse patients with these T cell armies (adoptive therapy).
Additional current translational effects focus on the ability of off-the-shelf chemotherapy agents in conjunction with Toll-like receptor agonists to cure far advanced and metastatic syngeneic mouse tumor models. Basically, this strategy tricks the immune system into mistaking cancer cells for an immediately life-threatening infection, ramping up the urgency with which the immune system recognizes malignancies. This shift in urgency enables the modulation of MDSCs into accessory cells with potent tumoricidal function.
A clinical trial implementing this strategy to treat cancer patients, including melanoma patients, is undergoing late stages of institutional approval and has already been approved by the Food and Drug Administration.
Close collaborations both within and external to Mayo Clinic have assured that the translational efforts of Dr. Cohen's team can propagate effectively. Within Mayo Clinic Cancer Center, Dr. Cohen collaborates with Sandra J. Gendler, Ph.D.; Leif Bergsagel, M.D.; and Marta Chesi, Ph.D.
International collaborators include Mary J. (Nora) Disis, M.D., at the Fred Hutchinson Cancer Research Center; James H. Finke, Ph.D., at the Cleveland Clinic Lerner Research Institute; Brian J. Czerniecki, M.D., Ph.D., at the University of Pennsylvania; and Walter J. Storkus, Ph.D., at the University of Pittsburgh.
- Optimal immunotargeting of the MUC1 gene for pancreatic cancer. Dr. Cohen and Dr. Gendler are co-principal investigators of a study within the Mayo Clinic Specialized Program of Research Excellence (SPORE) grant in pancreatic cancer. The long-term goal of this study is to optimize MUC1-directed immunotherapy by reversing tolerance and increasing functional avidity of anti-MUC1 CD4+ and CD8+ T cells in mice and humans with pancreatic cancer.
- Role of macrophage regulatory cells in immune regulation. With support from the National Institute of Allergy and Infectious Diseases, Dr. Cohen leads a study to evaluate the mechanisms by which regulatory cells of myeloid origin inhibit other cells, such as effector T cells, and evaluate the role of these in tumor promotion.
- Sunitinib modulation of cancer immunotherapy. Dr. Cohen and Dr. Finke led a recent study, funded by the National Cancer Institute, aimed at optimizing the use of the multiple receptor tyrosine kinase (multi-RTK) inhibitor sunitinib as an immunoadjuvant that ablates host myeloid-derived suppressor cells.
Significance to patient care
Dr. Cohen's work is leading to imminent clinical trials applicable to the treatment of most types of human cancer.