Glial injury in neurotoxicity after pediatric CD19-directed chimeric antigen receptor T cell therapy.
Glial injury in neurotoxicity after pediatric CD19-directed chimeric antigen receptor T cell therapy.
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DOI：
10.1002/ana.25502
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发表时间：
2019-07
影响因子：
11.2
通讯作者：
中科院分区：
文献类型：
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作者：
检测嵌合抗原受体（CAR）-T细胞治疗儿童和年轻人后免疫效应细胞相关神经毒性综合征（ICANS）中全身细胞因子释放是否与中枢神经系统炎症反应和神经胶质损伤相关。我们对43名年龄1至25岁的受试者进行了一项前瞻性队列研究，包括临床表现以及成像、病理学、CSF和血液生物标志物，这些受试者接受了CD 19导向的CAR/T细胞治疗急性淋巴细胞白血病（ALL）。43例受试者中有19例（44%）发生神经毒性。9例受试者（21%）出现CTCAE 3级或4级神经系统症状，无神经毒性相关死亡。最常见的是可逆性谵妄、头痛、意识水平下降、震颤和癫痫发作。康奈尔小儿谵妄评估（CAPD）评分≥9分，对≥3级神经毒性的敏感性为94%，特异性为33%，对≥2级神经毒性的敏感性为91%，特异性为72%。神经毒性与细胞因子释放综合征的严重程度、既往脑磁共振成像（MRI）异常和血液中较高的峰值CAR-T细胞数量相关，但与脑脊液（CSF）无关。在神经毒性过程中，CSF中S100钙结合蛋白B和胶质细胞酸性蛋白水平升高，表明星形胶质细胞损伤。CSF白色血细胞、蛋白质、干扰素-γ（IFNγ）、白细胞介素（IL）-6、IL-10和颗粒酶B（Gz B）伴随升高，血清IFNγ、IL-10、Gz B、粒细胞巨噬细胞集落刺激因子、巨噬细胞炎性蛋白1 α和肿瘤坏死因子α伴随升高，但IL-6未升高。我们没有发现内皮激活的直接证据。我们的数据与ICANS作为一种全身炎症综合征最为一致，它通过神经血管单元的损害和星形胶质细胞损伤来影响大脑。
To test whether systemic cytokine release is associated with central nervous system inflammatory responses and glial injury in immune effector cell-associated neurotoxicity syndrome (ICANS) after chimeric antigen receptor (CAR)-T cell therapy in children and young adults. We performed a prospective cohort study of clinical manifestations as well as imaging, pathology, CSF, and blood biomarkers on 43 subjects ages 1 to 25 who received CD19-directed CAR/T cells for acute lymphoblastic leukemia (ALL). Neurotoxicity occurred in 19 of 43 (44%) subjects. Nine subjects (21%) had CTCAE grade 3 or 4 neurological symptoms, with no neurotoxicity-related deaths. Reversible delirium, headache, decreased level of consciousness, tremor, and seizures were most commonly observed. Cornell Assessment of Pediatric Delirium (CAPD) scores ≥9 had 94% sensitivity and 33% specificity for grade ≥3 neurotoxicity, and 91% sensitivity and 72% specificity for grade ≥2 neurotoxicity. Neurotoxicity correlated with severity of cytokine release syndrome, abnormal past brain magnetic resonance imaging (MRI), and higher peak CAR-T cell numbers in blood, but not cerebrospinal fluid (CSF). CSF levels of S100 calcium-binding protein B and glial fibrillary acidic protein increased during neurotoxicity, indicating astrocyte injury. There were concomitant increases in CSF white blood cells, protein, interferon-γ (IFNγ), interleukin (IL)-6, IL-10, and granzyme B (GzB), with concurrent elevation of serum IFNγ IL-10, GzB, granulocyte macrophage colony-stimulating factor, macrophage inflammatory protein 1 alpha, and tumor necrosis factor alpha, but not IL-6. We did not find direct evidence of endothelial activation. Our data are most consistent with ICANS as a syndrome of systemic inflammation, which affects the brain through compromise of the neurovascular unit and astrocyte injury.
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影响因子：
20.3
作者：
Gardner, Rebecca A.;Finney, Olivia;Jensen, Michael C.
通讯作者：
Jensen, Michael C.
影响因子：
28.2
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
通讯作者：
Turtle CJ
影响因子：
82.9
作者：
Giavridis T;van der Stegen SJC;Eyquem J;Hamieh M;Piersigilli A;Sadelain M
通讯作者：
Sadelain M
DOI：
10.1111/bpa.12602
发表时间：
2018-05
期刊：
Brain pathology (Zurich, Switzerland)
影响因子：
--
作者：
Min R;van der Knaap MS
通讯作者：
van der Knaap MS
影响因子：
6
作者：
Gust J;Taraseviciute A;Turtle CJ
通讯作者：
Turtle CJ