Our Science – Wiltrout Website

Robert H. Wiltrout, Ph.D.

Laboratory of Experimental Immunology Head, Experimental Therapeutics Section Senior Investigator NCI-Frederick Bldg. 428, Room 46 Frederick, MD 21702 Phone:   (301) 846-1584 Fax:   301-846-6016 E-Mail:   wiltrour@mail.nih.gov

Biography

Dr. Robert Wiltrout obtained his Ph.D. in immunology from Wayne State University in 1979 and performed postdoctoral studies on the regulation of immune responses with Dr. Ronald Herberman at the NCI. He joined the Laboratory of Experimental Immunology in 1986. Dr. Wiltrout also serves as Director of the Center for Cancer Research and NIH Scientific Director for Basic Science.

Research

Innate and Adaptive Immune Mechanisms in Cytokine-Mediated Regression of Mouse Kidney and Breast Cancers

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 this regard, we have focused our efforts on several approaches to this hypothesis:

In particular, we are studying the immune regulating and cancer therapeutic potential of IL-12, IL-18, and the role of IFN-gamma in the innate and adaptive immune response; approaches for coordinating the innate and adaptive responses via stimulation of the CD40 receptor on antigen presenting cells in concert with IL-2 or IL-5 treatment; opportunities for simultaneous engagement of anti-angiogenesis and immune-based strategies for cancer treatment; and analyzing unique microenviromental dynamics and influences in the lungs and liver as a model for organ-specific immunotherapy.

In this context IL-12 and IL-18 play central regulatory roles for both innate and adaptive responses, and can synergize with IL-2 in several mouse kidney cancer models for T cell-dependent antitumor and antiangiogenic events that also depend on interferon gamma and/or TNF superfamily members. CD40, a TNF superfamily receptor serves as a potent trigger for dendritic cells which provide a key interface between innate and adaptive responses. The potency of dendritic cell stimulation by agonist CD40 antibodies is enhanced when used in conjunction with IL-2 and the combination of agonist anti-CD40 plus IL-2 shows enhanced antitumor activity against metastatic kidney cancer in mice. In addition, we have found that almost all renal cell carcinomas express functional CD40 and that ligation of CD40 on the tumor cells contributes to the beneficial effects of agonist CD40 therapy in vivo. These studies show that combination approaches that target different leukocyte subsets can result in greatly enhanced antitumor responses. These effects may be further increased by targeted disruption of other events in the tumor icroenvironment that directly favor tumor growth, or which may actively antagonize beneficial immune responses. In this regard, we have used hydrodynamic delivery of VEGFR, and VEGFR2 gene constructs to neutralize tumor-produced VEGF and impede tumor progression. Overall, these results suggest that combination strategies which activate appropriate immune response pathways and inhibit tumor-promoting pathways in the tumor microenvironment should lead to better therapies for cancer.

The liver, lungs and kidneys serve as unique model organs to understand the mechanisms by which parenchymal cells and leukocytes communicate in different microenvironments. These studies have relevance to understanding the regulation and optimization of development of innate immune responses and their relationship to metastasis formation and disease-induced inflammation. IL-12 and IL-18 are potent immunoregulatory cytokines for natural killer (NK), NKT, and T cells, and they induce beneficial antitumor activities in numerous experimental models. Our results have shown that although both IL-12 and IL-18 induced potent IFN-gamma-dependent antimetastatic effects, they have very distinctive effects on the NKT/NK subsets in different organs. In addition to studying the different immunoregulatory effects of cytokines on NKT and NK cells, we are also studying the interactions between these two subsets and the relative roles each plays in antitumor defenses.

The overall goal of our studies is to provide new insights into complex immune interactions in vivo and develop preclinical approaches for the use of immunotherapy, alone and in combination with other molecularly targeted strategies, for translation to clinical trials in cancer patients.

Collaborators on this project include John R. Ortaldo, Thomas J. Sayers, Jon M. Wigginton and Howard A. Young, NIH; William J. Murphy and Lisbeth Welniak, University of Nevada, Reno; Bruce Blazar, University of Minnesota; and Mark Smyth, Peter MacCallum Cancer Institute, Australia.

This page was last updated on 6/12/2008.