The molecular definition of tumor antigens has generated considerable enthusiasm for peptide-based cancer vaccines. As clinical efficacy remains limited, the focus of our research group is peptide-based cancer vaccine development. Using our innovative adoptive transfer model we have developed pre-clinical data for a novel vaccine delivery system that augments the primary T cell response via sustained paracrine release of antigenic peptide and cytokine(s). Furthermore, we have determined that post-vaccination T cell contraction is a major response limitation. Although programmed T cell contraction has been well described, the factors that modulate this response in the post-vaccination setting are not well defined. In this application we present preliminary data to suggest that the presence of a danger signal, alterations in the tissue microenvironment, and cytokine administration post-vaccination can modulate programmed T cell contraction. Given our expertise, and the ability of our adoptive transfer model to visualize the contraction phase, we are in the unique position to further these observations. The hypothesis of this grant proposal is that successful modulation of post-vaccination programmed T cell contraction will lead to enhanced antitumor immunity. In this proposal, we will use our adoptive transfer model to precisely define the mechanisms of programmed T cell contraction and the impact of specific danger signals (alpha GalCer and poly I:C) on this process. We will characterize the role of tissue microenvironment and altered T cell trafficking on post-vaccination T cell contraction and describe the impact of myeloablative conditioning regimens on the same. Further, we will delineate the impact of postvaccination systemic cytokine administration (IL-2, IL-15, and type 1 interferon) on programmed T cell contraction and define the impact of dose, timing of administration, and combination therapy on vaccine efficacy. We will then validate the most efficacious of these approaches in the poorly immunogenic TRP-2 murine melanoma model. Defining the factors that modulate programmed T cell contraction will provide critical information required for the design of more effective peptide vaccine strategies.
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