The molecular definition of tumor antigens has generated considerable enthusiasm for peptide-based cancer vaccines. However, the antigen-specific T cell response to peptide-based cancer vaccines remains poorly understood. The applicant has established an effective collaboration at the Medical University of South Carolina to explore the rational development of these vaccines. He has characterized a vaccine delivery system based on the unique polymer poly-N-acetyl glucosamine (designated F2 gel). This highly purified polysaccharide can be formulated into a stable matrix in combination with antigenic peptide and cytokine. F2 gel/peptide matrix vaccine is capable of effectively stimulating an antigen-specific T cell response, and is associated with protection from tumor challenge. Macrophages are critical to the efficacy of this vaccine, as macrophage depletion prior to vaccination abrogates the antigen-specific T cell response. The hypothesis of this application is that vaccination with the F2 gel/peptide/cytokine matrix leads to an effective cell-mediated antitumor response by providing sustained release of antigenic peptide and cytokine in a microenvironment that elicits macrophage activation. In this application, the applicant describes an innovative model based on the adoptive transfer of TCR transgenic OT-1 T cells and the murine tumor E.G7 that will allow him to precisely define in vivo T cell responses to peptide vaccination. He proposes to define whether a peptide-dose tolerance threshold exists which limits T cell antitumor responses and to evaluate whether paracrine cytokine release (Tc cytokines IL-12 and IL-2, or GM-CSF) can enhance the efficacy of his system. In addition, he will evaluate the ability of this unique vaccine delivery system to overcome E.G7 tumor-induced T cell anergy. Parallel studies will investigate the macrophage and dendritic cell response to the F2 gel matrix vaccine. Two unique reagents will facilitate his efforts to define the antigen presenting cell response to vaccination: the Kb/SIINFEKL tetramer, specific for the OT-1 TCR, and the mAb 25-D1.16, specific for the Kb/SIINFEKL complex. The results gained from the proposed studies will contribute to the design of phase I clinical trials.
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