The main focus of the Laboratory of Basic Immunology, led by Andrew D. Weinberg, Ph.D., 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.
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.
Current Research Collaborations
Phase I Trial of a Monoclonal Antibody to OX40 in Patients with Advanced Cancer (R01CA109563; PI Brendan Curti, MD)
Full List of Publications
Andrew A. Weinberg, Ph.D.
Magdalena Kovacsovics-Bankowski, M.D.
Lisa Lukaesko, Ph.D.
Nick Morris, Ph.D.
Amy Moran, Ph.D.
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