CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade.
CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade.
复制标题
DOI：
10.1038/s41591-018-0041-7
复制
发表时间：
2018-06
期刊：
影响因子：
82.9
通讯作者：
Sadelain M
中科院分区：
文献类型：
--
作者：
Giavridis T;van der Stegen SJC;Eyquem J;Hamieh M;Piersigilli A;Sadelain M
靶向 CD19 的嵌合抗原受体 (CAR) 疗法是治疗难治性 B 细胞恶性肿瘤的有效方法，尤其是急性淋巴细胞白血病 (ALL)。虽然大多数患者在单次输注 CD19 CAR T 细胞后即可获得完全缓解，但这种治疗的广泛适用性受到严重细胞因子释放综合征 (CRS) 的阻碍，该综合征的特点是发烧、低血压和呼吸功能不全，与包括白细胞介素 6 (IL-6) 在内的血清细胞因子升高相关。 CRS 通常发生在 T 细胞输注后数天内，即 CAR T 细胞扩增高峰期。在 ALL 中，肿瘤负荷高的患者最常见且更严重。 CRS 可能对 IL-6 受体阻断有反应，但可能需要使用大剂量皮质类固醇进行进一步治疗，以遏制潜在的致命严重程度。改善治疗和预防性治疗需要更好地了解 CRS 的病理生理学，但迄今为止，这一点仍然难以捉摸。我们在这里报告了一种 CRS 小鼠模型，该模型在 CAR T 细胞输注后 2-3 天内形成，可能是致命的，并且对 IL-6 受体阻断有反应。我们发现，其严重程度不是由 CAR T 细胞衍生的细胞因子介导，而是由受体巨噬细胞产生的 IL-6、白介素-1 (IL-1) 和一氧化氮 (NO) 介导，这使得新的治疗干预成为可能。
Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially acute lymphoblastic leukemia (ALL). While a majority of patients will achieve a complete response following a single infusion of CD19 CAR T cells, the broad applicability of this treatment is hampered by severe cytokine release syndrome (CRS), which is characterized by fever, hypotension and respiratory insufficiency associated with elevated serum cytokines including interleukin-6 (IL-6). CRS usually occurs within days of T cell infusion at the peak of CAR T cell expansion. In ALL, it is most frequent and more severe in patients with high tumor burden. CRS may respond to IL-6 receptor blockade, but can require further treatment with high dose corticosteroids to curb potentially lethal severity. Improved therapeutic and preventive treatments require a better understanding of CRS physiopathology, which has so far remained elusive. We report here a murine model of CRS that develops within 2–3 days of CAR T cell infusion, may be lethal and is responsive to IL-6 receptor blockade. We show that its severity is mediated not by CAR T cell-derived cytokines but by IL-6, interleukin-1 (IL-1) and nitric oxide (NO) produced by recipient macrophages, which enables novel therapeutic interventions.
登录
查看更多内容
影响因子：
28.2
作者：
Gust J;Hay KA;Hanafi LA;Li D;Myerson D;Gonzalez-Cuyar LF;Yeung C;Liles WC;Wurfel M;Lopez JA;Chen J;Chung D;Harju-Baker S;Özpolat T;Fink KR;Riddell SR;Maloney DG;Turtle CJ
通讯作者：
Turtle CJ
DOI：
10.1038/nrclinonc.2017.148
发表时间：
2018-01
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Neelapu SS;Tummala S;Kebriaei P;Wierda W;Gutierrez C;Locke FL;Komanduri KV;Lin Y;Jain N;Daver N;Westin J;Gulbis AM;Loghin ME;de Groot JF;Adkins S;Davis SE;Rezvani K;Hwu P;Shpall EJ
通讯作者：
Shpall EJ
影响因子：
46.9
作者：
Maher, J;Brentjens, RJ;Sadelain, M
通讯作者：
Sadelain, M
DOI：
10.1038/nri3073
发表时间：
2011-10-14
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1056/nejmoa1407222
发表时间：
2014-10-16
期刊：
The New England journal of medicine
影响因子：
--
作者：
Maude SL;Frey N;Shaw PA;Aplenc R;Barrett DM;Bunin NJ;Chew A;Gonzalez VE;Zheng Z;Lacey SF;Mahnke YD;Melenhorst JJ;Rheingold SR;Shen A;Teachey DT;Levine BL;June CH;Porter DL;Grupp SA
通讯作者：
Grupp SA