Chimeric antigen receptor-T (CAR-T) cell immunotherapy constitutes a cornerstone in the management of patients with relapsed/refractory B-cell lineage lymphoid malignancies. Toxicities such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematotoxicity (ICAHT) have been recognized in the post-infusion period. The initial interplay between CAR-T cells and tumor cells, followed by cytokine release and the bystander activation of the innate immunity cells, result in endothelial cell injury. In the current review, the ongoing research regarding endothelial injury in CAR-T cell recipients is summarized. Various markers of endothelial injury have been investigated in CAR-T cell recipients, including markers of complement activation, such as soluble C5b-9, endothelial dysfunction (angiopoietin-2, VCAM1, ICAM-1), inflammation, and thrombosis (von Willebrand antigen, ADAMTS13, thrombomodulin). The expression level of these endothelial injury markers has been identified as impaired in CAR-T cell recipients, not only when compared with healthy controls but also among patients with severe CRS/ICANS and those with mild toxicities or without toxicities. Furthermore, the Endothelial Activation and Stress Index (EASIX) and modified versions of this score, calculated in the pre- and early post-infusion period, seem to predict development of severe toxicities, ICAHT, and, thus, poor overall survival in CAR-T cell patients. More data concerning the role of these endothelial injury markers and clinical outcomes in CAR-T cell settings are essential.
嵌合抗原受体T细胞（CAR-T）免疫疗法已成为复发/难治性B细胞系淋巴恶性肿瘤患者治疗的基石。输注后阶段已识别出细胞因子释放综合征（CRS）、免疫效应细胞相关神经毒性综合征（ICANS）及血液毒性（ICAHT）等不良反应。CAR-T细胞与肿瘤细胞的初始相互作用，随后引发的细胞因子释放及天然免疫细胞的旁观者激活，共同导致内皮细胞损伤。本综述总结了当前关于CAR-T细胞受者内皮损伤的研究进展。已在CAR-T细胞受者中研究了多种内皮损伤标志物，包括补体激活标志物（如可溶性C5b-9）、内皮功能障碍标志物（血管生成素-2、VCAM1、ICAM-1）、炎症标志物及血栓形成标志物（血管性血友病因子抗原、ADAMTS13、血栓调节蛋白）。研究证实这些内皮损伤标志物在CAR-T细胞受者中的表达水平存在异常，不仅与健康对照组相比存在差异，在发生严重CRS/ICANS的患者与轻度毒性或无毒性的患者之间也呈现显著不同。此外，在输注前及输注早期计算的内皮激活与应激指数（EASIX）及其改良版本，似乎能够预测严重毒性反应、ICAHT的发生，进而预示CAR-T细胞患者总体生存率不佳。关于这些内皮损伤标志物在CAR-T细胞治疗环境中的作用及其与临床结局的关联，仍需更多研究数据予以明确。
Endothelial Injury Following CAR-T Cell Immunotherapy for Hematological Malignancies
肿瘤(癌症)患者之家