Dana Farber Cancer Institute, Boston, MA.
J Natl Cancer Inst. 2019 Jul 1;111(7):646-654. doi: 10.1093/jnci/djz017.
Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary new form of immunotherapy for the treatment of hematologic malignancies. The two primary toxicities associated with CAR T-cell therapy include cytokine-release syndrome and neurotoxicity. Cytokine-release syndrome is generally self-limited but high-grade toxicities like hypotension and hypoxemia can be managed with agents that block the effects of IL-6, like tocilizumab, and/or corticosteroids. Although CAR T-cell therapy-associated neurotoxicity is a well-described clinical phenomenon, its pathophysiology remains inadequately understood; treatments and preventive strategies remain elusive. Animal models and clinical trial experience suggest the centrality of monocytes, endothelial dysfunction, and the blood-brain barrier in the development of CAR T-cell-associated neurotoxicity. Here we report what is known from preclinical models, clinical trials, and histopathologic studies regarding the pathophysiology of neurotoxicity, predictors of its incidence, and potential targets for the treatment and prevention of neurotoxicity.
嵌合抗原受体 (CAR) T 细胞疗法是一种治疗血液系统恶性肿瘤的革命性新型免疫疗法。与 CAR T 细胞疗法相关的两种主要毒性包括细胞因子释放综合征和神经毒性。细胞因子释放综合征通常是自限性的，但低血压和低氧血症等高级别毒性可以用 IL-6 阻滞剂（如托珠单抗）和/或皮质类固醇来治疗。尽管 CAR T 细胞疗法相关的神经毒性是一种已被充分描述的临床现象，但它的病理生理学仍未被充分理解；治疗和预防策略仍然难以捉摸。动物模型和临床试验经验表明，单核细胞、内皮功能障碍和血脑屏障在 CAR T 细胞相关神经毒性的发展中具有核心作用。在这里，我们报告了从临床前模型、临床试验和组织病理学研究中了解到的有关神经毒性的病理生理学、其发生率的预测因素以及治疗和预防神经毒性的潜在靶点的信息。
