Neutrophil activation and clonal CAR-T re-expansion underpinning cytokine release syndrome during ciltacabtagene autoleucel therapy in multiple myeloma

Shuangshuang Yang, Jie Xu, Yuting Dai, Shiwei Jin, Yan Sun, Jianfeng Li, Chenglin Liu, Xiaolin Ma, Zhu Chen, Lijuan Chen, Jian Hou, Jian-Qing Mi () and Sai-Juan Chen ()
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Shuangshuang Yang: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Jie Xu: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Yuting Dai: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Shiwei Jin: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Yan Sun: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Jianfeng Li: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Chenglin Liu: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Xiaolin Ma: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Zhu Chen: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Lijuan Chen: First affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital
Jian Hou: Ren Ji Hospital affiliated to Shanghai Jiao Tong University School of Medicine
Jian-Qing Mi: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Sai-Juan Chen: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-023-44648-3

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