Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells.
Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells.
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DOI：
10.1158/2159-8290.cd-17-0698
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发表时间：
2017-12
期刊：
影响因子：
28.2
通讯作者：
Turtle CJ
中科院分区：
文献类型：
--
作者：
Gust J;Hay KA;Hanafi LA;Li D;Myerson D;Gonzalez-Cuyar LF;Yeung C;Liles WC;Wurfel M;Lopez JA;Chen J;Chung D;Harju-Baker S;Özpolat T;Fink KR;Riddell SR;Maloney DG;Turtle CJ
在难治性B细胞恶性肿瘤患者中，淋巴细胞清除性化疗后输注靶向CD19的嵌合抗原受体（CAR）修饰的T（CAR - T）细胞可能会因神经系统不良事件（AEs）而变得复杂。在133名接受CD19 CAR - T细胞治疗的成年人中，我们发现急性淋巴细胞白血病、骨髓中高CD19⁺细胞、高CAR - T细胞剂量、细胞因子释放综合征以及预先存在的神经系统合并症与神经系统不良事件风险增加相关。有严重神经毒性的患者表现出内皮激活的迹象，包括弥散性血管内凝血、毛细血管渗漏和血脑屏障（BBB）通透性增加。通透性增加的血脑屏障无法保护脑脊液免受包括干扰素 - γ在内的高浓度全身性细胞因子的影响，干扰素 - γ会诱导脑血管周细胞应激及其内皮激活细胞因子的分泌。在一名死于神经毒性的患者大脑中发现了内皮激活和多灶性血管破坏。在随后发生≥4级神经毒性的患者中，治疗前内皮激活的生物标志物水平较高。
Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor (CAR)-modified T (CAR-T) cells can be complicated by neurologic adverse events (AEs) in patients with refractory B cell malignancies. In 133 adults treated with CD19 CAR-T cells we found that acute lymphoblastic leukemia, high CD19+ cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier (BBB) permeability. The permeable BBB failed to protect the CSF from high concentrations of systemic cytokines including IFN-γ, which induced brain vascular pericyte stress and their secretion of endothelium-activating cytokines. Endothelial activation and multifocal vascular disruption were found in the brain of a patient with fatal neurotoxicity. Biomarkers of endothelial activation were higher before treatment in patients who subsequently developed grade ≥4 neurotoxicity.