Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells
Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells
复制标题
DOI：
10.1038/s41591-018-0036-4
复制
发表时间：
2018-06-01
期刊：
影响因子：
82.9
通讯作者：
Bondanza, Attilio
中科院分区：
文献类型：
--
作者：
Norelli, Margherita;Camisa, Barbara;Bondanza, Attilio
在临床上，嵌合抗原受体修饰的T （CAR - T）细胞疗法经常与危及生命的细胞因子释放综合征（CRS）和神经毒性相关。由于缺乏适当的动物模型，理解这些病理的本质和开发治疗方法受到阻碍。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热和IL-6水平升高，这是CRS的标志。在CRS期间，人单核细胞是IL-1和IL-6的主要来源。因此，该综合征可通过单核细胞消耗或用托珠单抗阻断IL-6受体来预防。然而，托珠单抗未能保护小鼠免受延迟致死性神经毒性，其特征是脑膜炎症。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生存期。这些发现为解决神经毒性提供了一种治疗策略，并为更安全的CAR - T细胞疗法开辟了新的途径。
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.