IN VIVO EFFECTOR CELL RESPONSE TO PEPTIDE VACCINATION

描述：(申请人摘要)肿瘤抗原的分子定义 激起了人们对基于多肽的癌症疫苗的相当大的热情。 然而，抗原特异性T细胞对基于多肽的癌症疫苗的反应 人们对此仍然知之甚少。申请人已经建立了一个有效的 南卡罗来纳医科大学的合作探索 合理开发这些疫苗。他描述了一种疫苗交付的特征 基于独特聚合物聚N-乙酰氨基葡萄糖(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 结合抗原肽和细胞因子的基质。F2凝胶/多肽 基质疫苗能够有效地刺激抗原特异性T细胞 反应，并与保护免受肿瘤挑战有关。巨噬细胞 对该疫苗的效力至关重要，因为巨噬细胞在 接种疫苗可以消除抗原特异的T细胞反应。的假说 这一应用是用F2凝胶/肽/细胞因子矩阵接种 导致有效的细胞介导的抗肿瘤反应通过提供持续的 抗原肽和细胞因子在微环境中的释放 巨噬细胞激活。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式 以及小鼠肿瘤E.G7，这将使他能够准确地在体内定义T 细胞对多肽疫苗的反应。他建议定义一个 存在限制T细胞抗肿瘤反应的多肽剂量耐受阈值 并评价旁分泌细胞因子(TC细胞因子IL-12和 IL-2，或GM-CSF)可增强HIS系统的疗效。此外，他还将 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。平行研究将研究巨噬细胞 以及树突状细胞对F2凝胶基质疫苗的反应。两种独特的试剂 将有助于他确定抗原提呈细胞对 疫苗接种：针对OT-1 TCR的KB/SIINFEKL四聚体和mAb 25-D1.16，专用于KB/SIINFEKL复合体。从调查中获得的结果 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.