Diurnal rhythm in chimeric antigen receptor T cell effectiveness in an observational study of 715 patients

BACKGROUNDChimeric antigen receptor (CAR) T cells are a leading immunotherapy for refractory B cell malignancies; however, their effect is limited by toxicity and incomplete efficacy. Daily (circadian) rhythms in immune function may offer a lever to boost therapeutic success; however, their clinical relevance to CAR T cell therapy remains unknown.METHODSWe retrospectively analyzed CAR T cell survival and complications based on infusion time at 2 geographically distinct hospitals: Washington University School of Medicine in St. Louis, Missouri, USA (n = 384) and Oregon Health & Science University in Portland, Oregon, USA (n = 331) between January 2018 and March 2025. The primary outcome was 90-day overall survival (OS). Secondary outcomes included event-free survival (EFS), cytokine release syndrome (CRS), immune cell-associated neurotoxicity syndrome (ICANS), ICU admission, shock, respiratory failure, and infection. We quantified the independent relationship between infusion time and outcomes using multivariable mixed-effects logistic regression and time-to-event models, adjusting for patient, oncologic, and treatment characteristics.RESULTSThe therapeutic index of CAR-T cells inversely correlated with the timing of administration, with later infusions associated with lower effectiveness and more adverse outcomes. For each hour that CAR T cell treatment was delayed, the adjusted odds ratio (aOR) of 90-day mortality increased by 24% (aOR 0.76; 95% CI 0.64-0.88, P = 0.001), severe neurotoxicity by 17% (P = 0.023), and mechanical ventilation by 27% (P = 0.026). These temporal patterns were most pronounced in patients receiving CD19-targeting CAR T cell products. In contrast, we did not find an association between infusion time and severe CRS (aOR 0.99; 95% CI, 0.75-1.27; P = 0.92).CONCLUSIONTime of day is a potent and easily modifiable factor that could optimize CAR T cell clinical performance.