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

• Published in: Nature communications Vol. 15; no. 1; pp. 360 - 16
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.01.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/21; 13/31; 38/39; 38/77; 38/88; 38/91; 631/250/2504/223/1699; 631/250/251; 631/67/1990/804; 692/308/575; Antigens; Blood cancer; Cell activation; Chimeric antigen receptors; Cytokine Release Syndrome; Cytokines; Cytotoxicity; Humanities and Social Sciences; Humans; Immune system; Immunology; Janus Kinases; Leukocytes (neutrophilic); Lymphocytes; Lymphocytes T; Macrophages; Monocytes; multidisciplinary; Multiple myeloma; Multiple Myeloma - genetics; Multiple Myeloma - therapy; Neutrophil Activation; Neutrophils; Patients; Receptors; Receptors, Chimeric Antigen - genetics; Science; Science (multidisciplinary); Signal Transduction; Signatures; STAT Transcription Factors; Therapy; Toxicity; Transcriptomes
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-44648-3

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.