Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, 127 Dongming Road, Zhengzhou, 450008, China.
J Hematol Oncol. 2018 Sep 24;11(1):121. doi: 10.1186/s13045-018-0653-x.
Genetically modified T cells that express a chimeric antigen receptor (CAR) are opening a new frontier in cancer immunotherapy. CAR T cells currently are in clinical trials for many cancer types. Cytokine release syndrome (CRS) and neurotoxicities (CAR-related encephalopathy syndrome, CRES) are major adverse events limiting wide deployment of the CAR T cell treatment. Major efforts are ongoing to characterize the pathogenesis and etiology of CRS and CRES. Mouse models have been established to facilitate the study of pathogenesis of the major toxicities of CAR T cells. Myeloid cells including macrophages and monocytes, not the CAR T cells, were found to be the major cells mediating CRS and CRES by releasing IL-1 and IL-6 among other cytokines. Blocking IL-1 or depletion of monocytes abolished both CRS and CRES, whereas IL-6 blocker can ameliorate CRS but not CRES. Therefore, both IL-1 and IL-6 are major cytokines for CRS, though IL-1 is responsible for CRES. It was also demonstrated in the mouse models that blocking CRS does not interfere with the CAR T cell antitumor functions. We summarized new developments in the grading, modeling, and possible new therapeutic approaches for CRS and CRES in this review.
基因修饰的表达嵌合抗原受体 (CAR) 的 T 细胞正在为癌症免疫治疗开辟新的领域。CAR T 细胞目前正在许多癌症类型的临床试验中进行。细胞因子释放综合征 (CRS) 和神经毒性 (CAR 相关脑病综合征，CRES) 是限制 CAR T 细胞治疗广泛应用的主要不良事件。目前正在进行大量工作来描述 CRS 和 CRES 的发病机制和病因。已经建立了小鼠模型来促进对 CAR T 细胞主要毒性的发病机制的研究。研究发现，包括巨噬细胞和单核细胞在内的髓样细胞，而不是 CAR T 细胞，通过释放白细胞介素-1 (IL-1) 和白细胞介素-6 (IL-6) 等细胞因子，介导 CRS 和 CRES。阻断 IL-1 或耗尽单核细胞可消除 CRS 和 CRES，而 IL-6 阻滞剂可改善 CRS，但不能改善 CRES。因此，IL-1 和 IL-6 都是 CRS 的主要细胞因子，尽管 IL-1 是 CRES 的主要原因。在小鼠模型中还表明，阻断 CRS 不会干扰 CAR T 细胞的抗肿瘤功能。在这篇综述中，我们总结了 CRS 和 CRES 的分级、建模和可能的新治疗方法的新进展。
