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Chimeric Antigen Receptor T Cell–Mediated Neurotoxicity in Nonhuman Primates
Cancer Discovery ( IF 29.7 ) Pub Date : 2018-06-01 , DOI: 10.1158/2159-8290.cd-17-1368
Agne Taraseviciute 1, 2, 3 , Victor Tkachev 1, 2, 3 , Rafael Ponce 4 , Cameron J Turtle 2 , Jessica M Snyder 5 , H Denny Liggitt 5 , David Myerson 2, 6 , Luis Gonzalez-Cuyar 6 , Audrey Baldessari 7 , Chris English 7 , Alison Yu 1 , Hengqi Zheng 1, 3 , Scott N Furlan 1, 2, 3 , Daniel J Hunt 1 , Virginia Hoglund 1 , Olivia Finney 1 , Hannah Brakke 1 , Bruce R Blazar 8 , Carolina Berger 2 , Stanley R Riddell 2 , Rebecca Gardner 1 , Leslie S Kean 1, 2, 3 , Michael C Jensen 1, 2, 3
Affiliation  

Chimeric antigen receptor (CAR) T-cell immunotherapy has revolutionized the treatment of refractory leukemias and lymphomas, but is associated with significant toxicities, namely cytokine release syndrome (CRS) and neurotoxicity. A major barrier to developing therapeutics to prevent CAR T cell–mediated neurotoxicity is the lack of clinically relevant models. Accordingly, we developed a rhesus macaque (RM) model of neurotoxicity via adoptive transfer of autologous CD20-specific CAR T cells. Following cyclophosphamide lymphodepletion, CD20 CAR T cells expand to 272 to 4,450 cells/μL after 7 to 8 days and elicit CRS and neurotoxicity. Toxicities are associated with elevated serum IL6, IL8, IL1RA, MIG, and I-TAC levels, and disproportionately high cerebrospinal fluid (CSF) IL6, IL2, GM-CSF, and VEGF levels. During neurotoxicity, both CD20 CAR and non-CAR T cells accumulate in the CSF and in the brain parenchyma. This RM model demonstrates that CAR T cell–mediated neurotoxicity is associated with proinflammatory CSF cytokines and a pan–T cell encephalitis.

Significance: We provide the first immunologically relevant, nonhuman primate model of B cell–directed CAR T-cell therapy–mediated CRS and neurotoxicity. We demonstrate CAR and non-CAR T-cell infiltration in the CSF and in the brain during neurotoxicity resulting in pan-encephalitis, accompanied by increased levels of proinflammatory cytokines in the CSF. Cancer Discov; 8(6); 750–63. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 663



中文翻译:


嵌合抗原受体 T 细胞介导的非人灵长类神经毒性



嵌合抗原受体 (CAR) T 细胞免疫疗法彻底改变了难治性白血病和淋巴瘤的治疗,但与显着的毒性相关,即细胞因子释放综合征 (CRS) 和神经毒性。开发预防 CAR T 细胞介导的神经毒性的疗法的一个主要障碍是缺乏临床相关模型。因此,我们通过过继转移自体 CD20 特异性 CAR T 细胞开发了恒河猴 (RM) 神经毒性模型。环磷酰胺淋巴细胞清除后,CD20 CAR T 细胞在 7 至 8 天后扩增至 272 至 4,450 个细胞/μL,并引发 CRS 和神经毒性。毒性与血清 IL6、IL8、IL1RA、MIG 和 I-TAC 水平升高以及脑脊液 (CSF) IL6、IL2、GM-CSF 和 VEGF 水平不成比例地升高相关。在神经毒性期间,CD20 CAR 和非 CAR T 细胞在脑脊液和脑实质中积累。该 RM 模型表明 CAR T 细胞介导的神经毒性与促炎性 CSF 细胞因子和泛 T 细胞脑炎相关。


意义:我们提供了第一个免疫学相关的非人灵长类动物模型,用于 B 细胞定向 CAR T 细胞疗法介导的 CRS 和神经毒性。我们证明了在导致全脑炎的神经毒性过程中,CSF 和大脑中的 CAR 和非 CAR T 细胞浸润,并伴随着 CSF 中促炎细胞因子水平的增加。癌症发现; 8(6); 750–63。 ©2018 AACR。


这篇文章在本期特稿中重点介绍,第 17 页。第663章

更新日期:2018-06-01
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