Robert H. Wiltrout
     Graduate student
     Adviser: Philip Frost
     Degree: Ph.D., 1979
     Title of thesis: In vivo and in vitro cell-mediated immune responses elicited by a
           metastatic murine tumor

Contact information (as of 12/1/03):
     NCI-FCRF
     P.O. Box B
     Bldg. 428, Rm. 46
     Frederick, MD 21702-1201
     Ph: (301) 846-1584
     Fax: (301) 846-1673
     Work email: wiltroutr@ncifcrf.gov
     Home email: NA

Links to Robert at NCI:
     NCI-FCRF#1
     NCI-FCRF#2

Current activity: I received a B.A. degree from Kutztown University, PA in 1972, a M.S. in Microbiology from the Pennsylvania State University, University Park, PA in 1975, and a Ph.D. in Immunology from Wayne State in 1979. I was awarded a United States Public Health Services fellowship in 1979 and performed postdoctoral studies at the NIH in the Laboratory of Immunodiagnosis with Dr. Ronald B. Herberman. In 1981, I studied briefly in Dr. Robert Kerbel's laboratory at Queens University in Kingston Ontario, Canada and also became a Staff Fellow in the newly formed Biological Response Modifiers Program at the National Cancer Institute Frederick Cancer Research and Development Center (NCI FCRDC), Frederick, MD. Since 1986 I have served as Head of the Experimental Therapeutics Section of the Laboratory of Experimental Immunology at the NCI at Frederick, and also served as a Deputy Director for the Center for Cancer Research at NCI.. In 2002, I was also appointed as the Associate Director, National Cancer Institute at Frederick. I have been Visiting Professor of Immunology at the University of Rome, Rome, Italy. I am a member of the American Association of Immunology, the American Association of Cancer Research, the Society for Leukocyte Biology, the Society for Natural Immunity, and the Society for Biological Therapy.

Present Research: The mechanisms by which the immune system can mediate tumor regression in vivo are complex and incompletely understood. Successful induction of cytokine-induced tumor regression may depend on a complex interplay between critical elements of the innate immune system (dendritic cells and NK or NK T cells) and classical elements of the adaptive immune response such as CD4+ or CD8+ T cells. In particular successfully engaged innate mechanisms may trigger inflammatory events in the tumor microenvironment that, in turn, provide instructive signals for the development of adaptive responses. Our general hypothesis is that the limited success of antigen-specific therapeutic approaches for patients with kidney cancer (and likely other tumors) derives at least partially from a lack of effective engagement of these early innate mechanisms that initiate and/or support the development of antigen-specific responses. In that regard IL-2, IL-12, and IL-18 all play central regulatory roles for both innate and adaptive immune responses, reciprocally regulate each other's receptors, and synergize for a variety of immune responses including IFN-gamma production, which is central for many of the biological effects of these cytokines. In addition, it may be possible to coordinately engage innate and adaptive responses by directly stimulating key antigen presenting cells (dendritic cells) while at the same time stimulating the T cell compartment.
     We have recently demonstrated that the combinations of IL-2 plus IL-12 and IL-2 plus IL-18 exhibit therapeutic synergy against orthotopic mouse kidney and/or breast cancers. In these settings, the mechanisms of early antiangiogenic effects and later tumor regression share a common dependency on IFN-gamma and the Fas/FasL pathway. In addition, we have also used anti-CD40 stimulation in combination with IL-2 to induce potent, tumor-specific adaptive responses against mouse kidney cancers. Our present efforts are focused on the molecular and cellular events that are vital for the initial phases of cytokine-induced tumor response. In particular, these studies seek to understand the role of the tumor cells versus supporting elements or host leukocytes in the regulation of local gene expression, effector cell recruitment, endothelial and tumor cell apoptosis, and ultimate regression of the tumor. In addition, because both kidney and breast cancers can metastasize to major parenchymal organs in mouse models and patients, studies are under way to delineate organ-specific differences in the regulation of innate immune responses in the lungs versus the liver. The emphasis of these studies is on organ-specific differences in cytokine-induced gene expression in organ-associated innate effector cells (e.g., NK and NK T cells and macrophages) and parenchymal cells unique to those different organ microenvironments, differences in recruitment and maintenance of leukocyte subsets in those organs, and unique cellular and molecular mechanisms for antimetastatic responses. An additional unique aspect of these studies is the use of new gene therapeutic approaches in which naked DNA plasmids encoding cytokine genes can now be delivered so effectively that cytokine protein levels and activities in vivo approach levels achieved after high-dose bolus administration of recombinant cytokines.
     Overall, these studies seek to identify critical events that regulate the recruitment and antitumor functions of innate immune mechanisms in tumor microenvironments and different anatomical sites, and provide a framework for using innate immunity to amplify antigen-specific adaptive immune antitumor response, and translate these strategies to new clinical trials for cancer treatment.