Altered MHC ligand vaccine design

改变 MHC 配体疫苗设计

• 批准号: 8581761
• 负责人: LARRY R PEASE
• 金额: $ 22.42万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-10 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8581761
• 关键词: Address; Affinity; Amino Acids; Animals; Antigen-Presenting Cells; Antigens; Binding; Cancer Patient; Cellular Immunity; Clinical Trials; Complex; Data; Development; Engineering; Environment; Experimental Designs; Exploratory/Developmental Grant; Funding; Future; Germ Lines; Goals; Human; Immune; Immune Tolerance; Immune response; Immunity; In Situ; In Vitro; Killer Cells; Knowledge; Learning; Lesion; Ligands; Maintenance; Major Histocompatibility Complex; Malignant Neoplasms; Mediating; Molecular; Mus; Nature; Patients; Peptide T; Peptide Vaccines; Peptides; Positioning Attribute; Pre-Clinical Model; Property; Regulatory T-Lymphocyte; Scheme; Signal Pathway; Signal Transduction; Specificity; Staging; Stimulus; Structure; Surface; System; T-Cell Activation; T-Cell Receptor; T-Cell Receptors alpha-Chain; T-Lymphocyte; TCR Activation; Testing; Time; Translating; Translations; Triad Acrylic Resin; Tumor Antigens; Vaccine Design; Vaccines; Variant; Viral; Viral Vector; base; cancer immunotherapy; design; high reward; high risk; in vivo; insight; mutant; neoplastic cell; novel; patient population; preclinical evaluation; public health relevance; receptor; receptor binding; three dimensional structure; tumor; vaccine development

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.

描述（由申请人提供）：该提案旨在测试一种针对弱抗原激活T淋巴细胞的新方法，并开发一种将这种新激活剂递送到动物（最终是人类）中以治疗已确定的癌症的方法。调节免疫耐受的基本机制是选择T细胞库，消除表达对自身具有强反应性的受体的T细胞。然而，仍然存在表达具有弱反应性的受体的T细胞，其不能被弱抗原（如存在于肿瘤上的抗原）激活。众所周知，一旦这些幼稚T细胞接收到强大的激活信号，它们就可以在随后遇到肿瘤时成为有能力的杀伤细胞。我们的实验设计是基于详细的结构知识磨练了超过30年的研究，定义了受体-配体相互作用之间的差异，在宽容和激活状态。我们建议在与T细胞受体（TcRs）的种系编码部分相互作用的主要组织相容性复合体（MHC）编码分子界面处的保守氨基酸中进行结构改变，测试这些改变的MHC以增强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/高回报的建议，我们将（1）测试的假设，即MHC配体可以产生激活正常耐受性T细胞的自身反应性，在体外和体内的属性，和（2）开发和测试病毒载体能够在体内传递抗原特异性刺激信号。来自R21机制的支持对于解决这些关键问题至关重要，并将提供所需的信息，这些信息将是未来使用临床前模型进行研究的基础，以及随后使用类似配制用于临床试验的人类HLA分子进行翻译的基础。维持抗原特异性，而不需要个性化每种疫苗， 给定的患者或肿瘤类型允许该平台成为“现成的”治疗，从而使各种癌症患者受益。