Engineering T Cell Receptors for Optimal Targeting of Established Tumors

摘要-项目3 通常用于监测异常表达的细胞内抗原的T细胞在 如果它们是自动反应的，就会发展。许多致癌突变只会导致微小的自我偏离。 主要组织相容性复合体(MHC)的产物呈递给T细胞的表位。因此，T 胸腺发育和选择后保留的细胞库主要由低亲和力受体组成 抗潜在的肿瘤抗原。为了克服肿瘤特异性T细胞谱系中的这一缺陷，各种 实验室已经尝试将编码肿瘤特异性T细胞受体的基因转移到患者的T细胞中 体外实验。与这些努力相一致，TCR被设计成对肽/MHC具有更高的亲和力 抗原。我们的基本假设是，这些高亲和力的TCR可以用于治疗癌症，无论是在 过继T细胞疗法或作为可溶性靶向分子(类似于单抗)。而当 这些方法显示出了希望，但关于它们的最佳使用仍然存在重大问题。目的 该项目将解决这些问题，并因此与该计划中的其他项目进行交互， 直接将这些发现应用于几种不同的肿瘤模型。该项目将利用我们广泛的 早期对涉及CTL克隆2C的小鼠系统的研究，以及一组具有 已经被设计成一系列的亲和力。该项目的具体目标将由 伊利诺伊大学的David Kranz的具体目标是：1.检查TCR2C的结合特性 这将使转导的T细胞获得最佳的特异性、外周扩增、存活和活性。特定的 目的2.探索提高基因导入外源TCRs表面水平的各种策略 转导。

Abstract - Project 3 T cells, which normally function to monitor for aberrantly expressed intracellular antigens, are deleted during development if they are autoreactive. Many tumorigenic mutations result in only minor deviations from self in the epitopes presented to T cells by products of the major histocompatibility complex (MHC). Hence, the T cell repertoire that remains after thymic development and selection consists largely of low-affinity receptors against potential tumor antigens. To overcome this deficiency in the tumor-specific T cell repertoire, various labs have attempted to transfer genes that encode a tumor-specific a(3 T cell receptor into a patient's T cells ex vivo. In concert with these efforts, TCRs have been engineered for higher affinities against peptide/MHC antigens. Our principle hypothesis is that these high-affinity TCRs can be used to treat cancer, either in adoptive T cell therapies or as soluble targeting molecules (by analogy to monoclonal antibodies). While these approaches show promise, significant questions remain regarding their optimal use. The purpose of this project is to address these questions, and thereby to interface with other projects in this program that will directly apply the findings to several different tumor models. The project will make use of our extensive earlier studies in the mouse system involving CTL clone 2C, and a collection of 2C TCR mutants that have already been engineered with a range of affinities. The specific aims of the project that will be directed by David Kranz at the University of Illinois are: Specific Aim 1. To examine the binding properties of TCR 2C that result in optimal specificity, peripheral expansion, survival, and activity of transduced T cells. Specific Aim 2. To explore various strategies to increase the surface levels of exognous TCRs introduced by gene transduction.