嵌合抗原受体 T 细胞疗法在实体瘤中的应用。

Chimeric antigen receptor T cells therapy in solid tumors.

机构信息

Faculty of Medicine, Yarmouk University, Irbid, Jordan.

Forensic and Toxicology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.

出版信息

Clin Transl Oncol. 2023 Aug;25(8):2279-2296. doi: 10.1007/s12094-023-03122-8. Epub 2023 Feb 28.

Abstract

Chimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. Chimeric antigen receptor (CAR) is an engineered synthetic receptor of CAR-T, which give T cells the ability to recognize tumor antigens in a human leukocyte antigen-independent (HLA-independent) manner and enables them to recognize more extensive target antigens than natural T cell surface receptor (TCR), resulting in tumor destruction. CAR-T is composed of an extracellular single-chain variable fragment (scFv) of antibody, which serves as the targeting moiety, hinge region, transmembrane spacer, and intracellular signaling domain(s). CAR-T has been developing in many generations, which differ according to costimulatory domains. CAR-T therapy has several limitations that reduce its wide availability in immunotherapy which we can summarize in antigen escape that shows either partial or complete loss of target antigen expression, so multiplexing CAR-T cells are promoted to enhance targeting of tumor profiles. In addition, the large diversity in the tumor microenvironment also plays a major role in limiting this kind of treatment. Therefore, engineered CAR-T cells can evoke immunostimulatory signals that rebalance the tumor microenvironment. Using CAR-T therapy in treating the solid tumor is mainly restricted by the difficulty of CAR-T cells infiltrating the tumor site, so local administration was developed to improve the quality of treatment. The most severe toxicity after CAR-T therapy is on-target/on-tumor toxicity, such as cytokine release syndrome (CRS). Another type of toxicity is on-target/off-tumor toxicity which originates from the binding of CAR-T cells to target antigen that has shared expression on normal cells leading to damage in healthy cells and organs. Toxicity management should become a focus of implementation to permit management beyond specialized centers.

摘要

嵌合抗原受体 T 细胞疗法(CAR-T 疗法)是一类过继性细胞免疫疗法。嵌合抗原受体(CAR)是 CAR-T 的一种工程合成受体,赋予 T 细胞以非人类白细胞抗原(HLA)依赖性方式识别肿瘤抗原的能力,并使其能够识别比天然 T 细胞表面受体(TCR)更广泛的靶抗原,从而导致肿瘤破坏。CAR-T 由抗体的单链可变片段(scFv)的细胞外区、铰链区、跨膜区和细胞内信号域组成。CAR-T 已经发展了多代,根据共刺激结构域的不同而有所区别。CAR-T 疗法存在一些限制,使其在免疫疗法中的广泛应用受到限制,我们可以总结为抗原逃逸,表现为靶抗原表达的部分或完全丧失,因此促进了多价 CAR-T 细胞以增强对肿瘤特征的靶向性。此外,肿瘤微环境的巨大多样性也在限制这种治疗方法中发挥了主要作用。因此,工程化 CAR-T 细胞可以引发免疫刺激信号,从而重新平衡肿瘤微环境。CAR-T 疗法在治疗实体瘤中的主要限制是 CAR-T 细胞浸润肿瘤部位的困难,因此开发了局部给药以改善治疗质量。CAR-T 治疗后最严重的毒性是靶标/肿瘤毒性,如细胞因子释放综合征(CRS)。另一种毒性是靶标/肿瘤外毒性,它源于 CAR-T 细胞与靶抗原的结合,靶抗原在正常细胞上有共同表达,导致健康细胞和器官受损。毒性管理应成为实施的重点,以允许在专门中心之外进行管理。

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