Divisions of Hematology and Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
Immunol Rev. 2019 Jul;290(1):114-126. doi: 10.1111/imr.12768.
The advent of chimeric antigen receptor T (CAR-T) and the burgeoning field of cellular therapy has revolutionized the treatment of relapsed/refractory leukemia and lymphoma. This personalized "living therapy" is highly effective against a number of malignancies, but this efficacy is tempered by side effects relatively unique to immunotherapies, including CAR-T. The overwhelming release of cytokines and chemokines by activated CAR-T and other secondarily activated immune effector cells can lead to cytokine release syndrome (CRS), which can have clinical and pathophysiology similarities to systemic inflammatory response syndrome and macrophage activating syndrome/hemophagocytic lymphohistiocytosis. Tocilizumab, an anti-IL6 receptor antibody, was recently FDA approved for treatment of CRS after CAR-T based on its ability to mitigate CRS in many patients. Unfortunately, some patients are refractory and additional therapies are needed. Patients treated with CAR-T can also develop neurotoxicity and, as the biology is poorly understood, current therapeutic interventions are limited to supportive care. Nevertheless, a number of recent studies have shed new light on the pathophysiology of CAR-T-related neurotoxicity, which will hopefully lead to effective treatments. In this review we discuss some of the mechanistic contributions intrinsic to the CAR-T construct, the tumor being treated, and the individual patient that impact the development and severity of CRS and neurotoxicity. As CAR-T and cellular therapy have redefined the concept of personalized medicine, so too will personalization be necessary in managing the unique side effects of these therapies.
嵌合抗原受体 T 细胞（CAR-T）的出现和细胞疗法的兴起彻底改变了复发/难治性白血病和淋巴瘤的治疗方法。这种个性化的“活体疗法”对多种恶性肿瘤具有高度疗效，但由于免疫疗法相对独特的副作用，包括 CAR-T，其疗效受到限制。激活的 CAR-T 和其他继发激活的免疫效应细胞过度释放细胞因子和趋化因子会导致细胞因子释放综合征（CRS），其临床表现和病理生理学与全身炎症反应综合征和巨噬细胞激活综合征/噬血细胞性淋巴组织细胞增多症相似。托珠单抗是一种抗白细胞介素 6 受体抗体，最近因其在许多患者中减轻 CRS 的能力而被 FDA 批准用于 CAR-T 治疗后的 CRS。不幸的是，一些患者对此类药物有抗药性，需要额外的治疗方法。接受 CAR-T 治疗的患者也可能出现神经毒性，由于其生物学机制尚未完全了解，目前的治疗干预措施仅限于支持性护理。然而，最近的一些研究揭示了 CAR-T 相关神经毒性的病理生理学的新见解，有望为其带来有效的治疗方法。在这篇综述中，我们讨论了 CAR-T 构建体、正在治疗的肿瘤和个体患者中一些固有机制对 CRS 和神经毒性的发展和严重程度的影响。随着 CAR-T 和细胞疗法重新定义了个性化医疗的概念，这些疗法的独特副作用的管理也需要个性化。
