Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, D-13092 Berlin, Germany.
Expert Opin Biol Ther. 2010 May;10(5):749-62. doi: 10.1517/14712591003689998.
Adoptive therapy with T cell receptor- (TCR-) redirected T cells has shown efficacy in mouse tumor models and first responses in cancer patients. One prerequisite to elicit effective anti-tumor reactivity is the transfer of high-avidity T cells. Their generation, however, faces several technical difficulties. Target antigens are often expressed at low levels and their recognition requires the use of high-affine receptors. Yet, mainly low-affinity TCRs have been isolated from tumor-infiltrating lymphocytes. Furthermore, upon transfer into a T cell the introduced receptor has to compete with the endogenous TCR.
This review discusses how the functional avidity of TCR-modified T cells can be enhanced by i) increasing the amount of introduced TCR heterodimers on the cell surface; and ii) generating receptors with high affinity. Risks of TCR gene therapy and possible safety mechanisms are discussed.
The reader will gain an overview of the technical developments in TCR and T cell engineering.
Despite technical obstacles, many advances have been made in the generation of high-avidity T cells expressing enhanced TCRs. Mouse studies and clinical trials will evaluate the effect of these improvements.
T 细胞受体（TCR）重定向 T 细胞的过继性治疗在小鼠肿瘤模型中显示出疗效，并在癌症患者中首次出现反应。引发有效抗肿瘤反应的一个前提条件是转移高亲和力 T 细胞。然而，它们的产生面临着几个技术难题。靶抗原通常表达水平低，其识别需要使用高亲和力受体。然而，主要是从肿瘤浸润淋巴细胞中分离出低亲和力 TCR。此外，在转移到 T 细胞中后，引入的受体必须与内源性 TCR 竞争。
这篇综述讨论了如何通过以下两种方式增强 TCR 修饰的 T 细胞的功能亲和力：i）增加细胞表面上引入的 TCR 异二聚体的数量；ii）产生具有高亲和力的受体。讨论了 TCR 基因治疗的风险和可能的安全机制。
读者将获得 TCR 和 T 细胞工程技术发展的概述。
尽管存在技术障碍，但在表达增强 TCR 的高亲和力 T 细胞的产生方面已经取得了许多进展。小鼠研究和临床试验将评估这些改进的效果。
