Robert H. Wiltrout, Ph.D.
Dr. Robert Wiltrout
Senior Investigator
Head, Experimental Therapeutics Section
Director, Center for Cancer Research and
CCR Scientific Director for Basic Research

The Experimental Therapeutics Section focuses on understanding the interactions within the tumor microenvironment between transplantable or oncogene-initiated de novo cancers and the immune system. Specifically, we focus on the balance between nascent, potentially beneficial, immune responses and the development of various immunosuppressive cells and cytokines that may facilitate tumor growth. Our goal is to develop intervention strategies that tip the balance toward immune-mediated tumor regression in syngeneic mouse models. Our approach has been to use both a well-described transplantable model(Renca) of renal cell carcinoma, as well as oncogene-initiated models of hepatocellular adenoma and carcinoma, and intrahepatic cholangiocarcinoma. In particular, the liver cancer models allow studies at all points along the tumor development continuum, from the first phase of transformation through all stages of progressive tumor growth. Our ultimate goal is to generate hypotheses and preclinical data that lay the groundwork for possible clinical immunotherapies against these relatively intractable cancers in humans.

Areas of Expertise
1) innate and adaptive immunology 2) kidney and liver cancer preclinical mouse models 3) combination immunotherapy 4) liver cancer biology

Contact Info

Robert H. Wiltrout, Ph.D.
Center for Cancer Research
National Cancer Institute
Building 428, Room 46 (Office)
Frederick, MD 21702-1201
301-846-1584
wiltrour@mail.nih.gov

Inflammation and Experimental Immunotherapy for Kidney and Liver Cancers in the Mouse Models

The mechanisms by which the immune system can contribute to promotion or inhibition of cancers in vivo are complex and incompletely understood. Successful induction of cytokine-induced tumor regression depends on a complex interplay between critical elements of the innate immune system (dendritic cells and NK or NKT cells) and classical elements of the adaptive immune response such as CD4+ or CD8+ T cells, and the ability to mitigate the immunosuppressive effects of T regulatory (Tregs), myeloid-derived suppressor cells (MDSC), and their active mediators. In particular, successfully engaged innate mechanisms may trigger inflammatory events in the tumor microenvironment that, in turn, minimize the effects of Tregs and MDSC, resulting in overall instructive signals for the development of beneficial adaptive responses. In this regard, we have focused our efforts on:

  1. The immune-regulating and cancer therapeutic potential of IL-12 and IL-18, and the role of IFN-gamma in the innate and adaptive immune response;
  2. Approaches for coordinating the beneficial effects of innate and adaptive responses with a mitigation of Treg and MDSC-mediated inhibitory effects via stimulation of the CD40 receptor on antigen presenting cells in concert with IL-2 or IL-15 treatment; and
  3. Understanding unique microenvironmental dynamics and influences in the lungs and liver as models for organ-specific immunotherapy.

We have also used Sleeping Beauty-mediated, in vivo genetic modification of hepatocytes with dysregulated AKT, MET, and beta-catenin genes to develop several reproducible, clinically-relevant, subtype-specific models of oncogene-initiated liver cancers and are using them to explore the intersection between oncogenesis and pathways of inflammation.  Our current effort is focused on the role of TNF-family members in the development and progression of oncogene-initiated liver cancers. In particular, we are investigating the role of activation through the lymphotoxin beta receptor (LTbetaR) on the biology of both hepatocellular adenomas and carcinomas, as well as the development of cholangiocarcinomas. Our current studies are focused on the downstream molecular signaling pathways and immune perturbations associated with the LTbetaR-dependent events and possible ways to modify liver tumor outcome through targeting of the LTbetaR.

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 Giorgio Trinchieri, John R. Ortaldo, Thomas J. Sayers, Snorri Thorgeirsson, Curt Harris, Perwez Hussain, David A. Wink, Xin Wang, and Howard A. Young, NIH; William J. Murphy, University of California at Davis; Bruce Blazar, University of Minnesota; Carl Ware, University of California, San Diego.

Scientific Focus Areas:
Cancer Biology, Immunology

View Dr. Wiltrout's PubMed Summary.

Selected Key Publications
  1. Weiss JM, Back TC, Scarzello AJ, Subleski JJ, Hall VL, Stauffer JK, Chen X, Micic D, Alderson K, Murphy WJ, Wiltrout RH.
    Proc. Natl. Acad. Sci. U.S.A. 106: 19455-60, 2009. [ Journal Article ]
  2. Weiss JM, Ridnour LA, Back T, Hussain SP, He P, Maciag AE, Keefer LK, Murphy WJ, Harris CC, Wink DA, Wiltrout RH.
    J. Exp. Med. 207: 2455-67, 2010. [ Journal Article ]
  3. Stauffer JK, Scarzello AJ, Andersen JB, De Kluyver RL, Back TC, Weiss JM, Thorgeirsson SS, Wiltrout RH.
    Cancer Res. 71: 2718-27, 2011. [ Journal Article ]
  4. Xiao Z, Jiang Q, Willette-Brown J, Xi S, Zhu F, Burkett S, Back T, Song N, Datla M, Sun Z, Goldszmid R, Lin F, Cohoon T, Pike K, Wu X, Schrump DS, Wong K, Young HA, Trinchieri G, Wiltrout RH, Hu Y.
    Cancer Cell. 23: 527-40, 2013. [ Journal Article ]
  5. Weiss JM, Subleski JJ, Back T, Chen X, Watkins SK, Yagita H, Sayers TJ, Murphy WJ, Wiltrout RH.
    J. Immunol. 192: 5821-29, 2014. [ Journal Article ]

Robert Wiltrout received his Ph.D. in Immunology and Microbiology from the Wayne State University Medical School and performed his postdoctoral studies with Dr. Ronald B. Herberman of the NIH. He joined the NCI in 1981 and in 1983 was promoted to tenured Senior Investigator and Head of the Experimental Therapeutics Section in the Laboratory of Experimental Immunology at the NCI-Frederick. In addition, he has served as NCI's Associate Director for NCI-Frederick and has been the Scientific Director for Basic Research and the Director of the Center for Cancer Research, NCI since 2005. Dr. Wiltrout is the holder of six patents in the area of immune response and hematopoietic regulation. He has been an organizer and/or plenary speaker at numerous national and international symposia in the areas of biological therapy of cancer, the regulation of immune responses in the tumor microenvironment, and mouse models of liver cancer. He is the author of more than 200 scientific publications in the areas of innate immunity, inflammation and cancer immunotherapy.

Name Position
Timothy Back Biological Laboratory Technician
Qun Jiang Ph.D. Research Fellow
John Ortaldo Ph.D. Expert
Anthony Scarzello Research Biologist
Jeffrey Subleski Research Biologist
Jonathan M. Weiss, Ph.D. Staff Scientist

Research

Inflammation and Experimental Immunotherapy for Kidney and Liver Cancers in the Mouse Models

The mechanisms by which the immune system can contribute to promotion or inhibition of cancers in vivo are complex and incompletely understood. Successful induction of cytokine-induced tumor regression depends on a complex interplay between critical elements of the innate immune system (dendritic cells and NK or NKT cells) and classical elements of the adaptive immune response such as CD4+ or CD8+ T cells, and the ability to mitigate the immunosuppressive effects of T regulatory (Tregs), myeloid-derived suppressor cells (MDSC), and their active mediators. In particular, successfully engaged innate mechanisms may trigger inflammatory events in the tumor microenvironment that, in turn, minimize the effects of Tregs and MDSC, resulting in overall instructive signals for the development of beneficial adaptive responses. In this regard, we have focused our efforts on:

  1. The immune-regulating and cancer therapeutic potential of IL-12 and IL-18, and the role of IFN-gamma in the innate and adaptive immune response;
  2. Approaches for coordinating the beneficial effects of innate and adaptive responses with a mitigation of Treg and MDSC-mediated inhibitory effects via stimulation of the CD40 receptor on antigen presenting cells in concert with IL-2 or IL-15 treatment; and
  3. Understanding unique microenvironmental dynamics and influences in the lungs and liver as models for organ-specific immunotherapy.

We have also used Sleeping Beauty-mediated, in vivo genetic modification of hepatocytes with dysregulated AKT, MET, and beta-catenin genes to develop several reproducible, clinically-relevant, subtype-specific models of oncogene-initiated liver cancers and are using them to explore the intersection between oncogenesis and pathways of inflammation.  Our current effort is focused on the role of TNF-family members in the development and progression of oncogene-initiated liver cancers. In particular, we are investigating the role of activation through the lymphotoxin beta receptor (LTbetaR) on the biology of both hepatocellular adenomas and carcinomas, as well as the development of cholangiocarcinomas. Our current studies are focused on the downstream molecular signaling pathways and immune perturbations associated with the LTbetaR-dependent events and possible ways to modify liver tumor outcome through targeting of the LTbetaR.

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 Giorgio Trinchieri, John R. Ortaldo, Thomas J. Sayers, Snorri Thorgeirsson, Curt Harris, Perwez Hussain, David A. Wink, Xin Wang, and Howard A. Young, NIH; William J. Murphy, University of California at Davis; Bruce Blazar, University of Minnesota; Carl Ware, University of California, San Diego.

Scientific Focus Areas:
Cancer Biology, Immunology

Publications

View Dr. Wiltrout's PubMed Summary.

Selected Key Publications
  1. Weiss JM, Back TC, Scarzello AJ, Subleski JJ, Hall VL, Stauffer JK, Chen X, Micic D, Alderson K, Murphy WJ, Wiltrout RH.
    Proc. Natl. Acad. Sci. U.S.A. 106: 19455-60, 2009. [ Journal Article ]
  2. Weiss JM, Ridnour LA, Back T, Hussain SP, He P, Maciag AE, Keefer LK, Murphy WJ, Harris CC, Wink DA, Wiltrout RH.
    J. Exp. Med. 207: 2455-67, 2010. [ Journal Article ]
  3. Stauffer JK, Scarzello AJ, Andersen JB, De Kluyver RL, Back TC, Weiss JM, Thorgeirsson SS, Wiltrout RH.
    Cancer Res. 71: 2718-27, 2011. [ Journal Article ]
  4. Xiao Z, Jiang Q, Willette-Brown J, Xi S, Zhu F, Burkett S, Back T, Song N, Datla M, Sun Z, Goldszmid R, Lin F, Cohoon T, Pike K, Wu X, Schrump DS, Wong K, Young HA, Trinchieri G, Wiltrout RH, Hu Y.
    Cancer Cell. 23: 527-40, 2013. [ Journal Article ]
  5. Weiss JM, Subleski JJ, Back T, Chen X, Watkins SK, Yagita H, Sayers TJ, Murphy WJ, Wiltrout RH.
    J. Immunol. 192: 5821-29, 2014. [ Journal Article ]

Biography

Robert Wiltrout received his Ph.D. in Immunology and Microbiology from the Wayne State University Medical School and performed his postdoctoral studies with Dr. Ronald B. Herberman of the NIH. He joined the NCI in 1981 and in 1983 was promoted to tenured Senior Investigator and Head of the Experimental Therapeutics Section in the Laboratory of Experimental Immunology at the NCI-Frederick. In addition, he has served as NCI's Associate Director for NCI-Frederick and has been the Scientific Director for Basic Research and the Director of the Center for Cancer Research, NCI since 2005. Dr. Wiltrout is the holder of six patents in the area of immune response and hematopoietic regulation. He has been an organizer and/or plenary speaker at numerous national and international symposia in the areas of biological therapy of cancer, the regulation of immune responses in the tumor microenvironment, and mouse models of liver cancer. He is the author of more than 200 scientific publications in the areas of innate immunity, inflammation and cancer immunotherapy.

Team

Name Position
Timothy Back Biological Laboratory Technician
Qun Jiang Ph.D. Research Fellow
John Ortaldo Ph.D. Expert
Anthony Scarzello Research Biologist
Jeffrey Subleski Research Biologist
Jonathan M. Weiss, Ph.D. Staff Scientist