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

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.

Long-term remission and survival in patients with relapsed or refractory multiple myeloma after treatment with LCAR-B38M CAR T cells: 5-year follow-up of the LEGEND-2 trial

“…Therefore, it is reasonable that patients with diseases that arise later in life, such as CLL and MM, are more susceptible to somatic mutagenesis. This has been observed by both our previous study and that of Fraietta’s study [ 37 , 38 ], in which, acquired TET2 mutations identified in elderly MM and CLL promoted CAR T expansion. Indeed, the four MM patients in this work respectively developed SPM at the age of 73, 68, 63, and 52 years old, consistent with age as a key risk factor for SPM.…”