T 细胞参与免疫疗法，突出嵌合抗原受体 (CAR) T 细胞疗法

发表日期：2022-01-17

T Cell Engaging Immunotherapies, Highlighting Chimeric Antigen Receptor (CAR) T Cell Therapy

The ultimate goal of T cell-engaging immunotherapy is to endorse the activity of a person’s own cytotoxic T cells in the tumor microenvironment, finally destroying cancer cells. Several types of immunotherapy are either approved for use or are under study in clinical trials to determine their effectiveness in treating various types of cancer. Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging in the field and has shown unprecedented success in the treatment of hematological malignancies. It entails the collection of a patient’s T cells to genetically engineer them in the lab to express CARs that target surface antigens on tumors to help identify and eradicate the tumor. However, major issues remain to be solved to enable generalized CART cell therapies in the clinic. Novel approaches to tackle these problems are being developed rapidly and are reviewed in this publication.

T 细胞参与免疫疗法的最终目标是认可一个人自身的细胞毒性 T 细胞在肿瘤微环境中的活性，最终摧毁癌细胞。几种类型的免疫疗法要么被批准使用，要么正在临床试验中进行研究，以确定它们在治疗各种癌症方面的有效性。嵌合抗原受体 (CAR) T 细胞疗法在该领域迅速兴起，并在治疗血液系统恶性肿瘤方面取得了前所未有的成功。它需要收集患者的 T 细胞，在实验室中对其进行基因工程改造，以表达靶向肿瘤表面抗原的 CAR，以帮助识别和根除肿瘤。然而，在临床上实现通用 CART 细胞疗法的主要问题仍有待解决。

细胞工厂

In addition to routinely applied procedures such as surgery, radiotherapy, and chemotherapy, immunotherapy is becoming a standard approach for cancer treatment. The most frequently used cancer immunotherapy approaches are summarized in Figure 1 and were recently reviewed [1,2]. Cancer immunotherapy aims to promote the activity of cytotoxic T cells within the tumor microenvironment by assisting in the priming of cytotoxic T cells in lymphoid organs and by establishing an efficient and durable antitumor immune response. Generally, three types of T cell-engaging immunotherapies are currently applied in the clinic: immune checkpoint inhibitors (ICI), bispecific T cell engagers (BiTEs), and genetically modified T cells, especially those expressing a chimeric antigen receptor (CAR). In this review, we briefly introduce ICI and BiTEs and mainly focus on the CAR T cell technology, which has lately innovated cancer immunotherapy. The latter strategy uses synthetic CARs to more specifically target cancer cells. Impressive progress has been made in the treatment of hematological malignancies, translated in the FDA approval of several CD19 CAR T therapies [3,4,5,6]. However, considerable challenges still remain for use of CAR T cell therapy to treat solid tumors, preventing them of being approved for use in the clinic. This is mainly due to the hostile tumor microenvironment and CAR-related toxicities, and many approaches have already been explored to overcome these obstacles, on which we further elaborate in the text.

除了手术、放疗和化疗等常规应用程序外，免疫疗法正在成为癌症治疗的标准方法。图 1总结了最常用的癌症免疫治疗方法，最近对其进行了综述 [ 1 , 2]。癌症免疫疗法旨在通过协助启动淋巴器官中的细胞毒性 T 细胞并建立有效且持久的抗肿瘤免疫反应来促进肿瘤微环境中细胞毒性 T 细胞的活性。一般来说，目前临床上应用了三种类型的 T 细胞参与免疫疗法：免疫检查点抑制剂 (ICI)、双特异性 T 细胞接合剂 (BiTE) 和转基因 T 细胞，尤其是那些表达嵌合抗原受体 (CAR) 的 T 细胞。在这篇综述中，我们简要介绍了 ICI 和 BiTE，主要关注最近为癌症免疫治疗带来创新的 CAR T 细胞技术。后一种策略使用合成 CAR 来更具体地靶向癌细胞。血液系统恶性肿瘤的治疗取得了令人瞩目的进展，3、4、5、6 ]。_ _ _ _ _ 然而，使用 CAR T 细胞疗法治疗实体瘤仍然存在相当大的挑战，从而阻止它们被批准用于临床。这主要是由于不利的肿瘤微环境和 CAR 相关的毒性，并且已经探索了许多方法来克服这些障碍，我们将在正文中进一步阐述。

三角细胞摇瓶

T cell-based cancer immunotherapies have emerged as a powerful tool in oncology. Nonetheless, it has taken many years of basic scientific research and subsequent translation to the clinic in order to demonstrate the power of immune system manipulation for the treatment of cancer. Further research into how T cells are regulated and their interplay with other immune cells such as DCs and NK cells will allow us to increase the strength of this approach even further. Thanks to the rapid development of genome editing technology, it is feasible to evaluate ambitious concepts, and to apply novel and often revolutionary clinical approaches. Although various challenges associated with CAR T cell therapy still remain to be solved, the overall great promise is supported by encouraging clinical results and the ongoing research in this field offers hope for the clinical application of cell therapies for cancer as routine rather than investigational strategies at the margins of frontline treatment.

高效摇瓶

基于 T 细胞的癌症免疫疗法已成为肿瘤学的有力工具。尽管如此，它还是需要多年的基础科学研究和随后的临床转化，才能证明免疫系统操作在治疗癌症方面的力量。进一步研究如何调节 T 细胞以及它们与其他免疫细胞（如 DC 和 NK 细胞）的相互作用将使我们能够进一步提高这种方法的强度。由于基因组编辑技术的快速发展，评估雄心勃勃的概念并应用新颖且经常是革命性的临床方法是可行的。尽管与 CAR T 细胞疗法相关的各种挑战仍有待解决。

关键词：chimeric antigen receptor,CAR, T cell,immunotherapy,嵌合抗原受体,汽车,T细胞,免疫疗法