Chief, Laboratory of Basic Immunology, Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute, Providence Health & Services
Adjunct Professor of Microbiology and Immunology, School of Medicine, Oregon Health Science University
Associate Clinical Professor of Neurology, School of Medicine, Oregon Health Science University
Research Interests
The main focus of the lab is to understand T cell activation during disease states. We have explored ways to manipulate the fate of antigen-specific T cells to enhance tumor-specific memory in hosts with cancer or downregulate antigen-specific responses in autoimmune disease. A challenge for immunologists has been to identify the antigen-specific cells within an inflammatory site and activate or downregulate their function in vivo. We have found a cell surface marker OX40 (CD134) that is expressed on the activated antigen-specific T cells within the site of inflammation, but not on peripheral T cells. This protein is a TNF-receptor family member that has potent costimulatory properties when crosslinked both in vitro and in vivo. We have used OX40 specific antibodies to expand tumor-reactive T cells in mice with cancer, ultimately resulting in a percentage of tumor-free mice. In contrast, we have used a deleting form of the OX40 antibody to destroy detrimental T cells in autoimmune disease, which ameliorates ongoing signs of clinical disease. By controlling the fate of antigen-specific T cells during inflammatory events, we are able to reduce or enhance T cell function in vivo, which ultimately alters the outcome of antigen-specific immunity. Currently, the lab has been trying to understand the intracellular mechanisms that lead to T cell survival once the OX40 receptor is engaged. Our goal is to enhance effector T cell survival in order to increase memory T cell development to maximize a long-term response to a particular antigen. Future projects include enhancing T cell memory to tumor antigens via OX40 agonists and performing immune-based analyses of a phase I clinical trial in cancer patients treated with anti-OX40.
Current Projects
The Laboratory of Basic Immunology has been studying the biologic function of the TNF-receptor family member, OX40, which has been shown by this group and others to enhance CD4 and CD8 T cell survival leading to increased memory. In particular, current research has shown that OX40 engagement in tumor-bearing hosts enhances anti-tumor immunity leading to destruction of tumors. The Laboratory of Basic Immunology has found that mice cured of tumors through OX40 engagement have tumor-specific memory T cells capable of eliciting potent anti-tumor immunity upon adoptive transfer into naïve mice.
Ongoing research efforts investigate the mechanism(s) involved with anti-OX40 mediated T cell survival in tumor-bearing hosts to further understand the link between increased tumor Ag-specific T cell survival and immune-mediated therapeutic efficacy. The specific aims of this research are as follows: 1) To understand the contribution that IL-12 makes to anti-OX40 enhanced tumor-specific T cell memory, 2) To elucidate the molecular basis for anti-OX40 enhancement of CD4 and CD8 T cell survival, and 3) To determine clinically relevant ways to elicit synergy between anti-OX40 and innate cytokines to enhance tumor-specific T cell memory and destruction of tumors. The knowledge gained from this study will help design more effective ways to enhance tumor immunotherapy, and ultimately gain a greater understanding of anti-OX40-specific therapy. OX40-specific augmentation of the immune system has recently increased in relevance, because the Laboratory of Basic Immunology has produced clinical grade anti-OX40 antibody and treated the first five cancer patients with this antibody as part of a phase I clinical trial.
