Altering Post Vaccination T Cell Contraction

描述（由申请人提供）：肿瘤抗原的分子定义引起了对基于肽的癌症疫苗的极大热情。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的开发。利用我们创新的过继转移模型，我们开发了一种新型疫苗递送系统的临床前数据，该系统通过持续的旁分泌释放抗原肽和细胞因子来增强原代T细胞反应。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。尽管程序性T细胞收缩已被很好地描述，但在接种疫苗后调节这种反应的因素尚未得到很好的定义。在这项应用中，我们提供了初步数据，表明危险信号的存在、组织微环境的改变和接种后细胞因子的施用可以调节程序性T细胞收缩。鉴于我们的专业知识，以及我们采用的转移模型可视化收缩阶段的能力，我们处于进一步观察这些观察的独特位置。这项拨款提案的假设是，成功调节接种后程序性T细胞收缩将导致抗肿瘤免疫增强。在本文中，我们将使用我们的过继传递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改变的T细胞运输在疫苗接种后T细胞收缩中的作用，并描述清髓调节方案对其的影响。此外，我们将描述接种后全身细胞因子（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、给药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.