Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Nonhuman Primates.
Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Nonhuman Primates.
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DOI：
10.1158/2159-8290.cd-17-1368
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发表时间：
2018-06
期刊：
影响因子：
28.2
通讯作者：
Jensen MC
中科院分区：
文献类型：
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作者：
Taraseviciute A;Tkachev V;Ponce R;Turtle CJ;Snyder JM;Liggitt HD;Myerson D;Gonzalez-Cuyar L;Baldessari A;English C;Yu A;Zheng H;Furlan SN;Hunt DJ;Hoglund V;Finney O;Brakke H;Blazar BR;Berger C;Riddell SR;Gardner R;Kean LS;Jensen MC
嵌合抗原受体（CAR）T细胞免疫疗法已经彻底改变了难治性白血病和淋巴瘤的治疗，但与显著的毒性相关，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治疗方法的主要障碍是缺乏临床相关模型。因此，我们通过自体CD 20特异性CAR T细胞的过继转移开发了神经毒性的恒河猴（RM）模型。环磷酰胺淋巴细胞耗竭后，CD 20 CAR T细胞在7-8天后扩增至272-4450个细胞/μl，并引发CRS和神经毒性。毒性与升高的血清IL-6、IL-8、IL-1 RA、TNF和I-TAC水平以及不成比例的高脑脊液（CSF）IL-6、IL-2、GM-CSF和VEGF水平相关。在神经毒性期间，CD 20 CAR和非CAR T细胞都在CSF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。
Chimeric Antigen Receptor (CAR) T cell immunotherapy has revolutionised 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 272–4450 cells/µl after 7–8 days and elicit CRS and neurotoxicity. Toxicities are associated with elevated serum IL-6, IL-8, IL-1RA, MIG and I-TAC levels, and disproportionately high cerebrospinal fluid (CSF) IL-6, IL-2, 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 pro-inflammatory CSF cytokines and a pan-T cell encephalitis.