Engineering T Cell Receptors for Optimal Targeting of Established Tumors

摘要-项目3 T细胞，其正常功能是监测异常表达的细胞内抗原，在免疫过程中被删除。 如果它们是自体反应的话。许多致瘤性突变仅导致与自身的微小偏差， 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 对抗潜在的肿瘤抗原为了克服肿瘤特异性T细胞库中的这种缺陷，各种免疫调节剂被用于治疗肿瘤特异性T细胞库。 实验室已经尝试将编码肿瘤特异性α 3 T细胞受体的基因转移到患者的T细胞中 离体。与这些努力相一致，TCR已经被工程化以针对肽/MHC具有更高的亲和力。 抗原我们的主要假设是，这些高亲和力TCR可用于治疗癌症，无论是在 过继性T细胞疗法或作为可溶性靶向分子（通过类比单克隆抗体）。而 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。的目的 本项目旨在解决这些问题，从而与本计划中的其他项目进行对接， 将这些发现直接应用于几种不同的肿瘤模型。该项目将利用我们广泛的 在小鼠系统中的早期研究涉及CTL克隆2C，以及一组2C TCR突变体， 已经被设计成具有一系列的亲和力。该项目的具体目标将由 伊利诺伊大学的大卫克兰兹的观点是：具体目标1。检测TCR 2C的结合特性 这导致转导T细胞的最佳特异性、外周扩增、存活和活性。具体 目标2.探索各种策略来增加基因导入的外源性TCR的表面水平， 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.