Molecular and Tumor Immunology Laboratory

Bernard A. Fox, Ph.D.

Bernard A. Fox, Ph.D.

The Laboratory of Molecular and Tumor Immunology, led by  Bernard A. Fox, Ph.D., 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. One answer to this is to create a lymphopenic host, reconstitute that host with lymphocytes and then inoculate with a tumor vaccine.

Other studies suggest that tumor-induced T regulating cells blunt the development of a therapeutic immune response. We have shown that depleting Treg cells from the cells used to reconstitute lymphopenic mice results in strikingly augmented anti-tumor immunity. A clinical trial of this strategy is currently underway in patients with melanoma. A third strategy we are investigating builds on pioneering work by our collaborator, Hong-Ming Hu, Ph.D., showing that autophagosome (DRibbles) contain antigens that can serve as highly-effective therapeutic cancer vaccines. Recent work in our lab is showing that vaccination with autophagosomes leads to protection from challenges with unrelated sarcomas. These results challenge a well-accepted paradigm in tumor immunology and provide insights into ways to improve cancer vaccines. These observations are already being translated into a clinical trial for patients with NSCLC.

Other members of the lab are evaluating changes in the immune system of patients on investigator-initiated clinical trials. One study has used protein arrays to define new targets present on cancer cells that are recognized by the immune system. Another has isolated RNA from circulating tumor cells obtained from patients with cancer, to investigate whether tumor markers targeted by the immune response are still expressed by the patient’s cancer.

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.

Current Research Collaborations

Melanoma - Exploiting Lymphopenia to Augment the Adoptive Immunotherapy of Melanoma Patients (RO1 CA119123, P.I. Bernard A. Fox, Ph.D.)

Clinical:
  • Walter J. Urba, M.D., Ph.D., director cancer research, Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute at Providence Cancer Institute
Lab:
  • Hong-Ming Hu, Ph.D., Laboratory of Cancer Immunobiology, Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute at Providence Cancer Institute

Adoptive Cellular Therapy in Melanoma

Clinical:
  • Walter J. Urba, M.D., Ph.D., director cancer research, Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute at Providence Cancer Institute
  • Brendan Curti, M.D., director of genitourinary oncology research, Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute at Providence Cancer Institute
Lab:
  • Hong-Ming Hu, Ph.D., Laboratory of Cancer Immunobiology, Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute at Providence Cancer Institute
  • Co-Investigators:
    • John T. Vetto, M.D. - Professor and Director of Cutaneous Oncology Program, Department of Surgery, OHSU
    • Kevin G. Billingsley, M.D. - Chief, Division of Surgical Oncology,  Associate Professor of Surgery, OHSU
    • Kelvin Yu, M.D. - surgical oncologist, The Oregon Clinic
    • John W. Smith II, M.D. - medical oncologist, US Oncology
    • William J. Wood, M.D. - surgical oncologist, Portland Surgical Associates
    • Steven K. Seung, M.D., Ph.D., director of radiation research, Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute at Providence Cancer Institute; radiation oncologist, The Oregon Clinic
    • Sidney Rosenheim, M.D., pathologist, Providence Portland Medical Center
    • Gary Grunkemeier, Ph.D., 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 J. Urba, M.D., Ph.D.)

Clinical:
  • Walter J. Urba, M.D., Ph.D., director cancer research, Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute at Providence Cancer Institute
  • Rachel Sanborn, M.D., co-medical director, Providence Thoracic Oncology Program, Providence Cancer Institute; medical oncologist, Providence Cancer Center Oncology and Hematology Clinic
Lab:
  • Hong-Ming Hu, Ph.D., Laboratory of Cancer Immunobiology, Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute at Providence Cancer Institute

Adjuvant therapeutic vaccination in patients with non-small cell lung cancer made lymphopenic and reconstituted with autologous PBMC

Clinical:

  • Ludwig-Maximilians University of Munich
    • Dominik Ruettinger, M.D.
    • Hauke Winter, M.D.
    • Natasha van den Engel, M.D.
    • Rudolf Hatz, M.D.  
Prostate - Development of effective immunotherapy for prostate cancer patients (DOD PC020094 – PI: Bernard A. Fox, Ph.D.)

Clinical:
  • Brendan Curti, M.D., director of genitourinary oncology research, Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute at Providence Cancer Institute

Exploiting lymphopenia and depletion of CD25+ regulatory T cells to augment effective immunotherapy (Prostate Cancer Foundation – PI: Bernard A. Fox, Ph.D.).

Clinical: 
  • Walter J. Urba, M.D., Ph.D., director cancer research, Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute at Providence Cancer Institute
  • Brendan Curti, M.D., director of genitourinary oncology research, Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute at Providence Cancer Institute

Breast - Clinical trial of DRibble vaccine in patients with breast cancer.

Clinical:
  • Walter J. Urba, M.D., Ph.D., director cancer research, Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute at Providence Cancer Institute
  • Rachel Sanborn, M.D., co-medical director, Providence Thoracic Oncology Program, Providence Cancer Institute; medical oncologist, Providence Cancer Center Oncology and Hematology Clinic
Lab:
  • Hong-Ming Hu, Ph.D., Laboratory of Cancer Immunobiology, Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute at Providence Cancer Institute
Ovarian - Autologous tumor vaccine with GM-CSF in patients with ovarian cancer

Collaboration:
  • Yili Wang, M.D.,  Xi’an Jiaotong University
Colorectal Cancer - A Phase II study of Active Immunotherapy With PANVACTM or Autologous, Cultured Dendritic Cells Infected With PANVACTM After Complete Resection of Hepatic OR Pulmonary Metastases of Colorectal Carcinoma

Clinical:
Full List of Publications

Laboratory Team

Bernard A. Fox, Ph.D.
Michael Afentoulis, M.S.
Sarah Church, M.S.
Shawn Jensen, Ph.D.
Michael LaCelle, M.S.
Tarsem Moudgil, M.S.
Sachin Puri, Ph.D.
Petra Schuberth, M.Sc.
Reineki van de Ven, Ph.D.
Chris Twitty, Ph.D.