Laboratory of Molecular and Tumor Immunology

Bernard A. Fox, Ph.D.

Phone: 503-215-6588
Fax: 503-215-6841
E-mail

Research and Academic Appointments

• Chief, Laboratory of Molecular and Tumor Immunology, Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute, Providence Health & Services
• Associate Professor, Molecular Microbiology and Immunology, Oregon Health and Science University School of Medicine
• Associate Professor, Biochemistry, and Molecular Biology, Oregon Graduate Institute of Science and Technology

Research Interests

The Laboratory of Molecular and Tumor Immunology hypothesizes that a primary reason for the failure of past tumor vaccine strategies is that the magnitude of the antitumor immune response is insufficient to mediate tumor regression. Our answer to this is to create a lymphopenic host, reconstitute that host with lymphocytes and then innoculate with a tumor vaccine. Our recent work with these reconstituted lymphopenic mice (RLM) documents the effectiveness of this strategy that augments priming of both tumor-specific CD8 and CD4 T cells.  While we have described the critical elements for successful vaccination in a normal “intact” host, preliminary studies suggest that the requirements for successful priming in the RLM host are strikingly different.  Defining the underlying mechanisms of successful priming in RLM hosts is an important focus of our current work.

Current Projects

Our own work, as well as that of others, has identified an approach for increasing the antitumor response that exploits the increased sensitivity of lymphocytes to respond to antigenic stimulae when they are placed under conditions of homeostasis-driven proliferation.  We modeled this by vaccinating lymphopenic mice with a GM-CSF gene-modified melanoma cell line (D5-G6) following reconstitution with naïve spleen cells. Subsequent examination of tumor vaccine-draining lymph node (TVDLN) T cells from reconstituted-lymphopenic mice (RLM) revealed a substantial increase in the frequency of activated T cells.  Following in vitro activation these T cells contained a significantly elevated frequency of tumor-specific CD4 and CD8 T cells with augmented function in vitro and therapeutic efficacy in vivo. When reconstitution was performed using spleen cells from systemic B16BL6-D5 (D5) tumor-bearing mice (TBM), anti-tumor function was lost.  However, depletion of CD25+ Treg cells from the spleen cells of TBM used for reconstitution led to recovery of tumor-specific function and therapeutic efficacy.

The Laboratory of Molecular and Tumor Immunology seeks to build on our extensive preclinical and clinical data in two proposed clinical trials.  The first is a randomized Phase II trial that will directly translate our preclinical observations and determine whether lymphopenic patients vaccinated with autologous tumor and GM-CSF, and reconstituted with either autologous total PBMC or CD25-depleted PBMC will generate a higher frequency of tumor-specific IFN-g secreting T cells.  This trial will allow us to “pick the winner”.  The second trial will use the winning strategy to induce tumor-specific T cells that will be harvested, activated and adoptively transferred back to the patient. 

Recent Publications

• He H, Wisner P, Yang G, Hu HM, Haley D, Miller W, O'Hara A, Alvord WG, Clegg CH, Fox BA, Urba WJ, Walker EB: Combined IL-21 and low-dose IL-2 therapy induces anti-tumor immunity and long-term curative effects in a murine melanoma tumor model. J Transl Med 2006, 4(1):24.
• Ruttinger D, Winter H, van den Engel NK, Hatz RA, Schlemmer M, Pohla H, Grutzner S, Schendel DJ, Fox BA, Jauch KW: Immunotherapy of lung cancer: an update. Onkologie 2006, 29(1-2):33-38.
• van den Engel NK, Winter H, Ruttinger D, Shau I, Schiller M, Mayer B, Moudgil T, Meimarakis G, Stolte M, Jauch KW, Fox BA, Hatz RA: Characterization of immune responses in gastric cancer patients: A possible impact of H. pylori to polarize a tumor-specific type 1 response? Clin Immunol. Epub 2006, 120(3): 285-96.

Current Research Collaborations

Melanoma

• Exploiting Lymphopenia to Augment the Adoptive Immunotherapy of Melanoma Patients (RO1 CA119123, P.I. Bernard Fox, PhD)
  • Clinical:
    • Walter J. Urba, MD, PhD - Director Cancer Research, Providence Portland Medical Center
  • Lab:
    • Hong-Ming Hu, PhD – Laboratory of Cancer Immunobiology
    • Edwin B. Walker, PhD - Laboratory of Immunological Monitoring
    • Christian Poehlein, MD – Laboratory of Molecular & Tumor Immunology

• Adoptive Cellular Therapy in Melanoma
  • Clinical:
    • Walter Urba, MD, PhD – Director of Cancer Research, Providence Portland Medical Center
    • Brendan Curti, MD – Director of Genitourinary Oncology Research, Providence Portland Medical Center
  • Lab:
    • Hong-Ming Hu, PhD – Laboratory of Cancer Immunobiology
    • Edwin Walker, PhD – Laboratory of Immunological Monitoring
    • Christian Poehlein, MD – Laboratory of Molecular & Tumor Immunology
  • Co-Investigators:
    • John T. Vetto, MD - Professor and Director of Cutaneous Oncology Program, Department of Surgery, OHSU
    • Kevin G. Billingsley, MD - Chief, Division of Surgical Oncology,  Associate Professor of Surgery, OHSU
    • Kelvin Yu, MD - Surgical Oncologist, Oregon Clinic
    • John W. Smith II, MD - Medical Oncologist, US Oncology
    • William J. Wood, MD - Surgical Oncologist, Portland Surgical Associates
    • Todd Crocenzi, MD, Director, Gastrointestinal Oncology Research, RWFCRC, EACRI, PPMC Medical Oncologist, the Oregon Clinic
    • Steven K. Seung, MD, PhD, Director of Radiation Research, RWFCRC, EACRI, PPMC, Radiation Oncologist, the Oregon Clinic
    • Sidney Rosenheim, MD, Pathologist Providence Portland Medical Center
    • Gary Grunkemeier, PhD, Director of the Medical Data Research Center, Providence St Vincent Medical Center

NSCLC

• Clinical Trial of Dribble Vaccine in NSCLC (R21 CA123864 pending PI: Walter Urba, MD) 
  • Clinical:
    • Walter Urba, MD – Director of Cancer Research, Providence Portland Medical Center
  • Lab: 
    • Hong-Ming Hu, PhD – Laboratory of Cancer Immunobiology
    • Edwin Walker, PhD – Immunological Monitoring Laboratory

• Adjuvant therapeutic vaccination in patients with non-small cell lung cancer made lymphopenic and reconstituted with autologous PBMC
  • Clinical:
    • Dominik Ruettinger, MD, Ludwig Maximilians University of Munich
    • Hauke, Winter, MD, Ludwig Maximilians University of Munich
    • Natasha van den Engel, MD, Ludwig Maximilians University of Munich
    • Rudolf Hatz, MD - Ludwig Maximilians University of Munich
  • Lab: 

    • Edwin Walker, PhD – Immunological Monitoring Laboratory

Prostate

• Development of effective immunotherapy for prostate cancer patients (DOD PC020094 – PI: Bernard Fox)
  • Clinical:
    • Brendan Curti, MD – Director of Genitourinary Oncology Research, Providence Portland Medical Center
• Exploiting lymphopenia and depletion of CD25+ regulatory T cells to augment effective immunotherapy (Prostate Cancer Foundation – PI: Bernard Fox). www.prostatecancerfoundation.org
  • Clinical: 
    • Walter Urba, MD, PhD – Director of Cancer Research, Providence Portland Medical  Center
    • Brendan Curti, MD – Director of Genitourinary Oncology Research, Providence Portland Medical Center
  • Lab:
    • Edwin Walker, PhD – Laboratory of Immunological Monitoring
    • Christian Poehlein, MD – Laboratory of Molecular & Tumor Immunology

Ovarian

• Autologous tumor vaccine with GM-CSF in patients with ovarian cancer
  • Collaboration: 
    • Yili Wang, MD,  Xi’an Jiaotong University

Colorectal Cancer

• A Phase II study of Active Immunotherapy With PANVACTM or Autologous, Cultured Dendritic Cells Infected With PANVAC^TM After Complete Resection of Hepatic OR Pulmonary Metastases of Colorectal Carcinoma
  • Clinical: 
    • Todd Crocenzi, MD – Director of Gastrointestinal Oncology Research, Providence Portland Medical Center

• Full list of publications
• Members of the laboratory
  
  
  

More Information

• Back to the Robert W. Franz Cancer Research Center