Innovative Immunotherapies Unit, San Raffaele Hospital Scientific Institute, Milano, Italy.
Vita-Salute San Raffaele University, Milano, Italy.
Nat Med. 2018 Jun;24(6):739-748. doi: 10.1038/s41591-018-0036-4. Epub 2018 May 28.
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.
在临床上，嵌合抗原受体修饰的 T 细胞（CAR T）疗法常伴有威胁生命的细胞因子释放综合征（CRS）和神经毒性。由于缺乏合适的动物模型，人们对这些病理的性质及其治疗方法的理解受到了阻碍。在此，我们描述了一种能够重现 CRS 和神经毒性关键特征的小鼠模型。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会引发高热和升高的白细胞介素-6（IL-6）水平，这些是 CRS 的标志。在 CRS 期间，人类单核细胞是白细胞介素-1（IL-1）和白细胞介素-6（IL-6）的主要来源。因此，通过单核细胞耗竭或用托珠单抗阻断 IL-6 受体可以预防该综合征。尽管如此，托珠单抗未能保护小鼠免受迟发性致命神经毒性的影响，其特征是脑膜炎症。相反，白细胞介素-1 受体拮抗剂阿那白滞素可消除 CRS 和神经毒性，从而显著延长无白血病生存时间。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 细胞疗法开辟了新途径。
