Department of Veterans Affairs - Career Development Award (CDA-2)
Surgical therapy has emerged as the mainstay of treatment for melanoma. Unfortunately, for patients with disease not amenable to surgical resection, effective oncological care is limited by the absence of effective systemic treatment options. Great effort has been directed toward the development of anti-melanoma immunotherapies, which take advantage of the fascinating ability of the immune system to (1) respond to a nearly limitless spectrum of foreign agents and (2) “remember” those agents against future encounters (so-called immunological memory). To date, attempts to orient the immune system to recognize, eliminate, and remember melanoma cells have been largely unsuccessful. It is theorized that an ability of melanoma to circumvent the immune system may be responsible for this clinical failure.
The overall hypothesis of my research effort is that growing melanoma tumors exert an active suppressive influence on the ability of immune cells to become fully activated to mount effective immune reactions and establish immunological memory. The existence of such an influence would clearly explain the failure of experimental immunotherapies to effectively treat melanoma. My previous scientific research training has included a postdoctoral research fellowship in the field of transplantation immunology, in which strategies to suppress the immune system are intentionally devised and investigated in an effort to prevent unwanted transplant organ rejection. My clinical training has included a fellowship in surgical oncology at the Memorial Sloan-Kettering Cancer Center. Since beginning my faculty appointment in August 2006, I have benefited enormously from an intensive network of scientific research mentorship that seeks to take advantage of this combined background in therapeutic immune suppression and surgical oncology, to investigate the phenomenon of cancer-induced immune suppression. I am also actively involved in the clinical care of veterans with melanoma and other cancers as a staff surgical oncologist at the William S. Middleton Veterans Administration Hospital in Madison, Wisconsin. Under the mentorship of Dr. Mark Albertini, an established VA investigator in the field of melanoma immunotherapy, and with the guidance of three non-VA mentor scientists in the field of oncology and immunology across the campus of the University of Wisconsin, I have recently developed a novel experimental animal model that not only confirms but also quantifies the ability of growing melanoma tumors to suppress the strength of acute immune responsiveness. In this proposal, I have outlined a plan to use this unique experimental system to answer fundamental questions about the impact of melanoma on the immune system. Specifically, I will work to identify basic cellular mechanisms underlying the immunosuppressive influence of melanoma. I will also modify this model to quantify the influence of melanoma on immunological memory. Finally, I will use the model to test the ability of immunomodulatory strategies to block the immunosuppressive influence of melanoma. I have also outlined a program of mentored professional career development that will take advantage of numerous resources at the University of Wisconsin to eventually become a fully independent scientific VA investigator.
By elucidating the nature and the mechanisms underlying melanoma-induced immune suppression, the ultimate goal of my research effort is to identify strategies with which this clinically undesirable phenomenon may be blocked. A discovery of this nature could allow us to finally realize the enormous but as yet theoretical potential of anti-cancer immunotherapy – which would offer veterans and other patients with melanoma a desperately needed strategy of systemic treatment that currently does not exist.