Altering Post Vaccination T Cell Contraction

肿瘤抗原的分子定义产生了相当大的热情肽为基础的癌症 疫苗。由于临床疗效仍然有限，我们的研究小组的重点是基于肽的癌症疫苗 发展使用我们创新的过继转移模型，我们已经开发了一种新的临床前数据。 通过持续的抗原性旁精细释放增强初级T细胞应答的疫苗递送系统 肽和细胞因子。此外，我们已经确定，疫苗接种后T细胞收缩是主要的 反应限制尽管程序性T细胞收缩已经被很好地描述，但调节T细胞收缩的因素仍然存在。 在接种后环境中的这种反应还没有很好地定义。在本申请中，我们提供了初步数据， 提示危险信号的存在，组织微环境的改变，以及细胞因子 接种后施用可调节程序性T细胞收缩。鉴于我们的专业知识， 我们的过继转移模型能够可视化收缩阶段，我们处于独特的地位，可以进一步 这些观察。这项拨款提案的假设是，成功地调节疫苗接种后 程序性T细胞收缩将导致增强的抗肿瘤免疫。在本提案中，我们将使用 我们的过继转移模型，以精确地定义程序性T细胞收缩的机制， 特定危险信号（α GalCer和poly I：C）对该过程的影响。我们将描述的作用， 组织微环境和改变的T细胞运输对接种后T细胞收缩的影响，并描述了 清髓性预处理方案的影响。此外，我们将描述后的影响- 对程序性T细胞的疫苗接种全身性细胞因子施用（IL-2、IL-15和1型干扰素） 收缩，并确定剂量、给药时间和联合治疗对疫苗的影响 功效然后，我们将在免疫原性差的TRP-2中验证这些方法中最有效的方法。 鼠黑素瘤模型。确定调节程序性T细胞收缩的因素将提供 设计更有效的肽疫苗策略所需的关键信息

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 paracfine 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 post- vaccination 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 immtmogenic 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