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.

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嵌合抗原受体（CAR）T细胞免疫疗法已彻底改变了难治性白血病和淋巴瘤的治疗方法，但与明显的毒性相关，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主要障碍是缺乏临床相关模型。因此，我们通过自体CD20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。环磷酰胺淋巴清除后，CD20 CAR T细胞在7至8天后膨胀至272至4,450细胞/μL，并引发CRS和神经毒性。毒性与血清IL6，IL8，IL1RA，MIG和I-TAC水平升高以及高比例的脑脊液（CSF）IL6，IL2，GM-CSF和VEGF水平相关。在神经毒性期间 CD20 CAR和非CAR T细胞都在CSF和脑实质中积聚。这种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pan-T细胞脑炎有关。

意义：我们提供了第一个与免疫相关的，非人类灵长类动物模型的B细胞定向CAR T细胞疗法介导的CRS和神经毒性。我们证明了在神经毒性导致全脑炎的同时，CSF和大脑中的CAR和非CAR T细胞浸润，伴随着CSF中促炎细胞因子水平的提高。巨蟹座Discov; 8（6）; 750–63。©2018 AACR。

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