IN VIVO EFFECTOR CELL RESPONSE TO PEPTIDE VACCINATION

描述：（申请人摘要）肿瘤抗原的分子定义 对基于肽的癌症疫苗产生了相当大的热情。 然而，对基于肽的癌症疫苗的抗原特异性T细胞应答 仍然知之甚少。申请人已建立有效的 南卡罗来纳州医科大学的合作， 合理开发疫苗。他描述了一次疫苗运送 基于独特的聚合物聚-N-乙酰葡糖胺（命名为F2）的系统 凝胶）。这种高度纯化的多糖可以配制成稳定的 基质与抗原肽和细胞因子的组合。F2凝胶/肽 基质疫苗能够有效地刺激抗原特异性T细胞 反应，并与保护肿瘤的挑战。巨噬 对这种疫苗的效力至关重要，因为在接种前 疫苗接种消除了抗原特异性T细胞应答。的假设 该应用是用F2凝胶/肽/细胞因子基质接种 导致有效的细胞介导的抗肿瘤反应， 在微环境中释放抗原肽和细胞因子， 巨噬细胞活化在本申请中，申请人描述了一种 基于TCR转基因OT-1 T细胞过继转移的创新模型 以及小鼠肿瘤E.G7，这将使他能够精确地定义体内T 细胞对肽疫苗接种的反应。他建议定义一个 存在限制T细胞抗肿瘤应答的肽剂量耐受阈值 并评估旁分泌细胞因子释放（Tc细胞因子IL-12和IL-14）是否与细胞因子的释放有关。 IL-2或GM-CSF）可以增强该系统的功效。另外他还会 评估这种独特的疫苗输送系统克服E.G7的能力 肿瘤诱导的T细胞无能。平行研究将调查巨噬细胞 和树突状细胞对F2凝胶基质疫苗的应答。两种独特的试剂 这将有助于他确定抗原呈递细胞对 疫苗接种：特异于OT-1 TCR的Kb/SIINFEKL四聚体和mAb 25-D1.16，特异于Kb/SIINFEKL复合物。结果表明， 拟议的研究将有助于I期临床试验的设计。

DESCRIPTION: (Applicant's Abstract) 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.