Altering Post Vaccination T Cell Contraction

描述（由申请人提供）：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。由于临床疗效仍然有限，我们研究小组的重点是基于肽的癌症疫苗开发。使用我们创新的过继转移模型，我们已经开发了一种新型疫苗递送系统的临床前数据，该系统通过抗原肽和细胞因子的持续旁分泌释放来增强原发性T细胞应答。此外，我们已经确定，接种后T细胞收缩是一个主要的反应限制。虽然程序性T细胞收缩已得到很好的描述，但在接种后环境中调节这种反应的因素尚未得到很好的定义。在本申请中，我们提出了初步数据，表明存在的危险信号，组织微环境的改变，以及接种后的细胞因子管理可以调节程序性T细胞收缩。鉴于我们的专业知识，以及我们的过继转移模型可视化收缩阶段的能力，我们处于独特的地位，可以进一步观察这些情况。这项拨款提案的假设是，疫苗接种后程序性T细胞收缩的成功调节将导致增强的抗肿瘤免疫力。在这项提案中，我们将使用我们的过继转移模型来精确定义程序性T细胞收缩的机制以及特定危险信号（α GalCer和poly I：C）对这一过程的影响。我们将描述组织微环境和T细胞运输改变对接种后T细胞收缩的作用，并描述清髓性预处理方案对其的影响。此外，我们将描述疫苗接种后全身性细胞因子管理（IL-2，IL-15和1型干扰素）对程序性T细胞收缩的影响，并确定剂量，管理时间和联合治疗对疫苗疗效的影响。然后，我们将在免疫原性较差的TRP-2小鼠黑色素瘤模型中验证这些方法中最有效的方法。确定调节程序性T细胞收缩的因素将为设计更有效的肽疫苗策略提供关键信息。

DESCRIPTION (provided by applicant): 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.