Altered MHC ligand vaccine design

改变 MHC 配体疫苗设计

• 批准号: 8660605
• 负责人: LARRY R PEASE
• 金额: $ 19.88万
• 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/8660605
• 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）：本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型激活剂输送到动物（最终是人类）体内的方法，以治疗已建立的癌症。调节免疫耐受的基本机制是T细胞库的选择，消除表达对自身反应性强的受体的T细胞。然而，仍然存在表达弱反应性受体的T细胞，不能被弱抗原激活（如肿瘤上存在的）。众所周知，一旦这些na - T细胞接收到强大的激活信号，它们就会在随后遇到肿瘤时变成称职的杀伤细胞。我们的实验设计是基于经过30多年研究的详细结构知识，这些研究定义了受体-配体相互作用在耐受性和激活状态下的差异。我们建议对主要组织相容性复合体（MHC）编码分子界面上与种系编码T细胞受体（TcR）相互作用区域的保守氨基酸进行结构改变，测试这些改变的MHC是否增强了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/高回报的提议中，我们将(1)在体外和体内测试MHC配体可以激活具有自身反应性的正常耐受T细胞的假设，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。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，这些信息将为未来使用临床前模型的研究奠定基础，并随后使用类似于临床试验的人类HLA分子进行翻译。维持抗原特异性，而不需要个性化每种疫苗