Abstract
BACKGROUND Chimeric 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.METHODS We 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.RESULTS The 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).CONCLUSION Time of day is a potent and easily modifiable factor that could optimize CAR T cell clinical performance.
Authors
Patrick G Lyons, Emily Gill, Prisha Kumar, Melissa Beasley, Brenna Park-Egan, Zulfiqar A. Lokhandwala, Katie M. Lebold, Brandon Hayes-Lattin, Catherine L. Hough, Nathan Singh, Guy Hazan, Huram Mok, Janice M. Huss, Colleen A. McEvoy, Jeffrey A. Haspel
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