Neutrophil activation and clonal CAR-T re-expansion underpinning cytokine release syndrome during ciltacabtagene autoleucel therapy in multiple myeloma.
Neutrophil activation and clonal CAR-T re-expansion underpinning cytokine release syndrome during ciltacabtagene autoleucel therapy in multiple myeloma.
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DOI：
10.1038/s41467-023-44648-3
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发表时间：
2024-01-08
影响因子：
16.6
通讯作者：
Chen, Sai-Juan
中科院分区：
文献类型：
--
作者：
Yang, Shuangshuang;Xu, Jie;Dai, Yuting;Jin, Shiwei;Sun, Yan;Li, Jianfeng;Liu, Chenglin;Ma, Xiaolin;Chen, Zhu;Chen, Lijuan;Hou, Jian;Mi, Jian-Qing;Chen, Sai-Juan
细胞因子释放综合征（CRS）是嵌合抗原受体重定向T细胞（CAR-T）治疗最常见的并发症。CAR-T毒性管理已得到极大改善，但CRS仍然是主要的安全性问题。在这里，我们纵向跟踪了26名接受CAR-T产品ciltacabtagene autoleucel的复发/难治性多发性骨髓瘤患者的血清细胞因子水平和循环免疫细胞转录组，以了解CRS的免疫动力学。我们发现，虽然T淋巴细胞和单核细胞/巨噬细胞是主要的整体细胞因子的来源，在明显的CRS，中性粒细胞活化高峰更早，严重的症状发作之前。在细胞内，JAK/STAT通路主导的信号激活发生在细胞因子级联反应之前，并显示出规律的动力学变化。CRS严重程度被准确描述，并可能通过时间细胞因子分泌特征预测。值得注意的是，在三名患者中发现了CAR-T再扩增，包括以体细胞TET 2突变、克隆扩增的细胞毒性CAR-T、扩大的细胞因子谱和不可逆的肝毒性为特征的致死性病例。总之，我们的研究结果表明，具有明显免疫学变化的潜伏期先于明显CRS，为CRS治疗干预提供了最佳窗口和潜在靶点，CAR-T再扩增需要密切的临床关注和实验室研究，以减轻致命风险。嵌合抗原受体T细胞（CAR-T）疗法已经彻底改变了血液癌症的治疗，然而，免疫相关的不良反应，如细胞因子释放综合征（CRS）可能会限制治疗的成功。在这里，作者表明CRS之前是一个潜伏期，其特征是中性粒细胞活化和不同的细胞因子特征，并且CAR-T再扩增可能与严重的CRS相关。
Cytokine release syndrome (CRS) is the most common complication of chimeric antigen receptor redirected T cells (CAR-T) therapy. CAR-T toxicity management has been greatly improved, but CRS remains a prime safety concern. Here we follow serum cytokine levels and circulating immune cell transcriptomes longitudinally in 26 relapsed/refractory multiple myeloma patients receiving the CAR-T product, ciltacabtagene autoleucel, to understand the immunological kinetics of CRS. We find that although T lymphocytes and monocytes/macrophages are the major overall cytokine source in manifest CRS, neutrophil activation peaks earlier, before the onset of severe symptoms. Intracellularly, signaling activation dominated by JAK/STAT pathway occurred prior to cytokine cascade and displayed regular kinetic changes. CRS severity is accurately described and potentially predicted by temporal cytokine secretion signatures. Notably, CAR-T re-expansion is found in three patients, including a fatal case characterized by somatic TET2-mutation, clonal expanded cytotoxic CAR-T, broadened cytokine profiles and irreversible hepatic toxicity. Together, our findings show that a latent phase with distinct immunological changes precedes manifest CRS, providing an optimal window and potential targets for CRS therapeutic intervention and that CAR-T re-expansion warrants close clinical attention and laboratory investigation to mitigate the lethal risk. Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized the treatment of hematological cancers, however, immune related adverse effects, such as cytokine release syndrome (CRS) may limit therapeutic success. Here authors show that CRS is preceded by a latent stage, characterized by neutrophil activation and distinct cytokine signatures, and that CAR-T re-expansion might associate with severe CRS.
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影响因子：
30.8
作者：
Busque L;Patel JP;Figueroa ME;Vasanthakumar A;Provost S;Hamilou Z;Mollica L;Li J;Viale A;Heguy A;Hassimi M;Socci N;Bhatt PK;Gonen M;Mason CE;Melnick A;Godley LA;Brennan CW;Abdel-Wahab O;Levine RL
通讯作者：
Levine RL
影响因子：
82.9
作者：
Giavridis T;van der Stegen SJC;Eyquem J;Hamieh M;Piersigilli A;Sadelain M
通讯作者：
Sadelain M
影响因子：
11.4
作者：
Arends, Christopher Maximilian;Galan-Sousa, Joel;Damm, Frederik
通讯作者：
Damm, Frederik
影响因子：
6
作者：
Casulleras M;Zhang IW;López-Vicario C;Clària J
通讯作者：
Clària J
影响因子：
82.9
作者：
Gabriel, Richard;Eckenberg, Ralph;Schmidt, Manfred
通讯作者：
Schmidt, Manfred