Building better T cell receptors for targeted immunotherapy

为靶向免疫治疗构建更好的 T 细胞受体

• 批准号: 9388963
• 负责人: Brian M Baker
• 金额: $ 72.07万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9388963
• 关键词: Adverse event; Affinity; Antigens; Binding; Biochemical; Biological Models; Biophysics; Cardiovascular system; Cellular Immunity; Cellular biology; Cessation of life; Clinical; Clinical Trials; Coupled; Data; Development; Engineering; Environment; Future; Gene-Modified; Goals; HLA-A2 Antigen; Immunologics; Immunotherapy; In Vitro; Ligands; MART-1 Tumor Antigen; Malignant Neoplasms; Measurement; Membrane; Modeling; Molecular Evolution; Mus; Muscle Proteins; Nature; Outcome; Patients; Peptides; Performance; Physiological; Property; Proteins; Publishing; Specificity; Structure; System; T-Cell Receptor; T-Cell Receptor Genes; T-Lymphocyte; T-cell receptor repertoire; Testing; Therapeutic; Toxic effect; Translations; Tumor Antigens; Tumor-Infiltrating Lymphocytes; Variant; Work; base; biophysical properties; clinically relevant; connectin; cross reactivity; design; experience; immunogenicity; improved; in vivo; infectious disease treatment; innovation; interest; melanoma; novel; programs; receptor binding; response; structural biology; therapy development; tumor

Project Summary / Abstract T cell receptors (TCRs) have emerged as a new class of immunological therapeutics. Clinical trials with TCR gene-modified T cells have shown that objective clinical responses can be obtained for patients with advanced malignancies. Similar approaches are in development for treatment of infectious disease. However, there is considerable debate over the nature of the TCR to be used in engineered T cells, and whether naturally occurring TCRs can be improved. Emphasis has been on identifying natural “high affinity” TCRs, and these have been emphasized in clinical trials. As T cell potency can sometimes be strengthened with the affinity of the TCR for antigen, there have also been efforts to use TCRs engineered for enhanced antigen affinity in immunotherapy. However, adverse events, including deaths, have occurred in some trials with gene-modified T cells. In some cases, this is clearly attributable to TCR cross-reactivity. Moreover, as high affinity can curtail function and low affinity TCRs are clearly functional, the presumption that improved TCR affinity is better for immunotherapy is questionable. In this multi-PI proposal, we propose an ambitious and innovative program to ask and answer how to build better TCRs for immunotherapy. Our overall hypothesis is that structure-guided design coupled with comprehensive in vitro and in vivo functional studies can be used to engineer TCRs for improved antigen recognition while limiting off-target cross-reactivity. To achieve this, we will combine the T cell biology and immunotherapy expertise of the Nishimura lab at Loyola with the TCR structure and biophysics expertise of the Baker lab at Notre Dame. We will also incorporate emerging concepts of “2D affinity” measurements and assess how they relate to specificity and other biophysical parameters, with 2D measurements to be performed by the Evavold lab at Emory. Using the MART1 tumor antigen as a model and beginning with the clinically relevant DMF5 TCR, we propose the following three aims: 1) Determine how structure-guided manipulations of TCR binding impact antigen recognition and in vivo function; 2) Generate improved TCR variants through iterative cycles of structure-guided design and biophysical/functional characterization, emphasizing the capacity to engineer specificity independently of affinity; 3) Assess the generalities of the lessons learned by applying the results from DMF5 to one or more unrelated MART1-specific TCRs. The completion of the aims will lead to a better understanding of how TCRs recognize antigen and how to most effectively engineer TCRs for optimal function in immunotherapy.

项目总结/摘要 T细胞受体（TCR）已经作为一类新的免疫治疗剂出现。TCR临床试验 基因修饰的T细胞已经表明，晚期乳腺癌患者可以获得客观的临床反应， 恶性肿瘤。类似的方法正在开发用于治疗传染病。不过有 关于将用于工程化T细胞中的TCR的性质以及天然存在的TCR是否具有生物学活性的争论， TCR可以改善。重点一直是鉴定天然的“高亲和力”TCR，并且这些TCR已经被广泛应用。 在临床试验中强调。由于T细胞效力有时可以用TCR对T细胞的亲和力来加强，因此， 除了抗原之外，还努力在免疫疗法中使用经工程改造以增强抗原亲和力的TCR。 然而，在一些基因修饰的T细胞试验中发生了包括死亡在内的不良事件。在一些 在某些情况下，这显然归因于TCR交叉反应性。此外，由于高亲和力可以削减功能和降低免疫原性， 尽管亲和力TCR是明确功能性的，但改善的TCR亲和力对于免疫治疗更好的假设是 值得怀疑在这个多PI提案中，我们提出了一个雄心勃勃的创新计划，以询问和回答如何 为免疫治疗构建更好的TCR。我们的总体假设是，结构导向设计加上 全面的体外和体内功能研究可用于工程化TCR以改善抗原 识别，同时限制脱靶交叉反应性。为了实现这一点，我们将联合收割机结合T细胞生物学和 洛约拉西村实验室的免疫治疗专业知识与TCR结构和生物物理学专业知识， 在圣母大学的贝克实验室。我们还将纳入新兴的概念“二维亲和力”测量和评估 它们与特异性和其他生物物理参数的关系， 埃默里大学的埃瓦沃德实验室。使用MART 1肿瘤抗原作为模型，并从临床相关的 DMF 5 TCR，我们提出了以下三个目标：1）确定如何结构指导的操作TCR 结合影响抗原识别和体内功能; 2）通过迭代产生改进的TCR变体 结构导向设计和生物物理/功能表征的循环，强调 独立于亲和力的工程师特异性; 3）通过应用 结果从DMF 5到一个或多个不相关的MART 1特异性TCR。目标的完成将导致 更好地理解TCR如何识别抗原以及如何最有效地工程化TCR， 在免疫治疗中的作用。