Altered MHC ligand vaccine design

描述(申请人提供)：这项提案旨在测试一种新的方法，以激活针对弱抗原的T淋巴细胞，并开发一种方法，将这种新的激活剂输送到动物(最终，人类)中，用于治疗已确定的癌症。调节免疫耐受的一个基本机制是选择T细胞库，清除表达对自身具有强烈反应性的受体的T细胞。然而，仍有表达受体的T细胞具有弱反应性，不能被弱抗原激活(与肿瘤上存在的一样)。众所周知，一旦这些NAéve T细胞接收到强大的激活信号，当它们随后遇到肿瘤时，它们就可以成为合格的杀伤细胞。我们的实验设计是基于30多年来研究中磨练出来的详细结构知识，这些研究定义了耐受状态和激活状态下受体-配体相互作用的差异。我们建议在与T细胞受体(TCR)的生殖系编码部分相互作用的区域中，对主要组织相容性复合体(MHC)编码分子界面上的保守氨基酸进行结构改变，测试这些改变的MHC是否有增强的TCR结合和强大的T细胞激活信号，同时保持定义抗原特异性的受体-配体相互作用的性质。在这个高风险/高回报的方案中，我们将(1)在体外和体内验证MHC配体可以产生具有激活具有自身反应特性的正常耐受T细胞的特性的假设，以及(2)开发和测试能够在体内传递抗原特异性刺激信号的病毒载体。来自R21机制的支持对于解决这些关键问题是必不可少的，并将提供所需的信息，这些信息将为未来使用临床前模型进行研究以及随后使用类似于临床试验配方的人类HLA分子进行翻译奠定基础。保持抗原特异性，而无需对每个疫苗进行个性化 特定的患者或肿瘤类型允许该平台因此成为一种“现成”疗法，使多种癌症患者受益。

DESCRIPTION (provided by applicant): This proposal is designed to test a novel way to activate T lymphocytes toward weak antigens and to develop a means to deliver this novel activator into animals (and ultimately, humans) for treating established cancers. A fundamental mechanism regulating immune tolerance is the selection of the T cell repertoire, eliminating T cells expressing receptors with strong reactivity against self. However, there still exist T cells expressing receptors with weak reactivity, not capable of being activated by weak antigens (as exist on tumors). It is well known that once these na¿ve T cells receive a robust activation signal they can become competent killer cells when they subsequently encounter tumors. Our experimental design is based on detailed structural knowledge honed over more than 30 years of studies that defined differences between receptor-ligand interactions in the tolerant and activation states. We propose to make structural changes in conserved amino acids at the interface of Major Histocompatibility Complex (MHC)-encoded molecules in regions that interact with germ-line encoded parts of T cell receptors (TcRs), testing these altered MHCs for enhanced TcR binding and robust T cell activation signals, while maintaining the nature of receptor-ligand interactions which define antigen specificity. In this high risk/high reward proposal, we will (1) test the hypothesis that MHC ligands can be generated with the property of activating normally tolerant T cells with autoreactive properties, in vitro and in vivo, and (2) develop and test a viral vector capable of delivering the antigen-specific stimulatory signal in vivo. Support from the R21 mechanism is essential for addressing these critical questions and will provide needed information that will be foundational for future studies using preclinical models and the subsequent translation using human HLA molecules similarly formulated for clinical trials. Maintenance of antigen specificity without needing to personalize each vaccine for a given patient or tumor type allows this platform to thereby be an "off the shelf" therapy to benefit a wide variety of cancer patients.