In the clinic, chimeric antigen receptor-modified T (CAR T) cell therapy is frequently associated with life-threatening cytokine-release syndrome (CRS) and neurotoxicity. Understanding the nature of these pathologies and developing treatments for them are hampered by the lack of appropriate animal models. Herein, we describe a mouse model recapitulating key features of CRS and neurotoxicity. In humanized mice with high leukemia burden, CAR T cell-mediated clearance of cancer triggered high fever and elevated IL-6 levels, which are hallmarks of CRS. Human monocytes were the major source of IL-1 and IL-6 during CRS. Accordingly, the syndrome was prevented by monocyte depletion or by blocking IL-6 receptor with tocilizumab. Nonetheless, tocilizumab failed to protect mice from delayed lethal neurotoxicity, characterized by meningeal inflammation. Instead, the IL-1 receptor antagonist anakinra abolished both CRS and neurotoxicity, resulting in substantially extended leukemia-free survival. These findings offer a therapeutic strategy to tackle neurotoxicity and open new avenues to safer CAR T cell therapies.

中文翻译：

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单核细胞衍生的IL-1和IL-6对于因CAR T细胞引起的细胞因子释放综合征和神经毒性有不同的需求。

在临床中，嵌合抗原受体修饰的T（CAR T）细胞疗法通常与威胁生命的细胞因子释放综合征（CRS）和神经毒性相关。缺乏适当的动物模型阻碍了对这些病理学性质的了解和针对它们的治疗方法。在这里，我们描述了一个小鼠模型，概括了CRS和神经毒性的关键特征。在具有高白血病负担的人源化小鼠中，CAR T细胞介导的癌症清除引发高烧和升高的IL-6水平，这是CRS的标志。人单核细胞是CRS期间IL-1和IL-6的主要来源。因此，通过单核细胞耗竭或通过用tocilizumab阻断IL-6受体可预防该综合征。然而，托珠单抗未能保护小鼠免受以脑膜炎症为特征的延迟致死性神经毒性。相反，IL-1受体拮抗剂anakinra消除了CRS和神经毒性，从而大大延长了无白血病的生存期。这些发现为治疗神经毒性提供了一种治疗策略，并为更安全的CAR T细胞疗法开辟了新途径。