Ryan Teague, Ph.D.

00002.00009

Assistant Professor

Ph.D., University of Kansas, 2002

Email: rteague@slu.edu

Phone: 314-977-8871

Research Summary:

T lymphocytes (T cells) represent a major arm of the immune system responsible for recognizing and eliminating cancer and infected cells. The ability of T cells to mediate anti-tumor effects in people is well documented, but harnessing this activity to provide a reliable therapeutic benefit has been challenging. The strategies for engaging T cell-mediated anti-tumor activity involve activating T cells through vaccination, or adoptively transferring tumor-reactive T cells following isolation and expansion in vitro. Many obstacles to success with these strategies have been identified, including selecting an appropriate tumor antigen to target, maintaining the response in the context of persistent antigen stimulation, and overcoming inhibitory and tolerizing pathways resulting from the tumor and the nature of the antigen being targeted. The research in my lab is aimed at understanding the immune response to tumors, with particular interest in leukemia, lymphoma, breast, and prostate cancer. Our goal is to engineer animal models and design experiments that allow us to address the issues relevant to the clinical translation of T cell-based immunotherapy for treatment of human cancer.

Project 1: Engineering a better anti-tumor CD8+ T cell

One of the primary reasons for failure of immunotherapy is the challenge of maintaining survival and efficacy of infused T cells, which are often deleted after infusion but before any beneficial anti-tumor/viral activity can be exacted. Our previous work demonstrated that expression of peripheral self-antigen is largely responsible for such deletion in mice, and that any T cells remaining from the deleted population are rendered tolerant; failing to expand upon subsequent antigen stimulation (Morimoto et al, J. Immunol. 2007). Thus, understanding how to prevent or overcome deletion and induction of tolerance in adoptively transferred CD8+ T cells could lead to improved outcomes for patients being treated for cancer or chronic viral infection. To this end, we recently showed that expression of a second T cell receptor (TCR) specific for a foreign protein (i.e. not a self/tumor-antigen) provided a means to expand and rescue function of tolerant CD8+ T cells in vivo (Teague et al, Immunity 2008). Such dual-TCR T cells could be expanded periodically via immunization through the second non-tolerized TCR by infusion of antigen presenting cells (APC) pulsed with appropriate peptide, and these rescued T cells provided resistance to subsequent challenge with live leukemic tumor. Although this work provided key insights into the fate of infused CD8+ T cells and the mechanisms that regulate induction and maintenance of CD8+ T cell tolerance, it did not specifically address the issues of preventing deletion or rescuing T cells for treatment of cancer. Thus, we are now exploring this strategy as a potential improvement to T cell-based immunotherapy by immunizing dual-TCR T cells in vivo via a second expressed receptor to maintain population size and effector function following adoptive transfer into leukemia-bearing recipients. We have also begun utilizing similar approaches to examine the utility of dual-TCR T cells for the treatment of chronic viral infections.

Project 2: Improving T cell-based immunotherapy of prostate cancer

T cell-based immunotherapeutic strategies have recently attracted increased interest as a means to treat prostate cancer, as cell-mediated immune responses have clearly been shown in some patients to actively suppress prostate tumor progression. However, the challenge of choosing which antigens to target for effective treatment does represent a substantive obstacle. Additionally the efficacy of T cell therapy even if an appropriate antigen is selected may be impeded the induction of tolerance, and/or by immunosuppressive regulatory cells, which have been shown to be induced by prostate tumors and to accumulate in developing tumor tissues and draining lymph nodes. Ultimately, the absence of curative therapies for advanced or recurrent forms of prostate cancer highlight the need for novel treatment strategies. My lab is engineering a unique animal model designed to examine issues vital to advancing the clinical translation of T cell vaccination and adoptive T cell therapy for treatment of solid tumors, and prostate cancer in particular. This model will be used to elucidate and overcome roadblocks to therapeutic efficacy, including providing insights for rationally selecting targets that are distinctly localized in subcellular compartments, and defining the utility of ablating regulatory T cells. The ultimate goals are to design and test strategies that can lead to the development of more effective T cell-based therapies of human prostate cancer, and potentially provide insights into improved treatments for other human malignancies.

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