Diurnal rhythms in chimeric antigen receptor T cell performance: an observational study of 670 patients

ABSTRACT Background Chimeric antigen receptor (CAR) T cells are a leading immunotherapy for refractory B-cell malignancies, but their impact is constrained by toxicity and incomplete long-term efficacy. Daily (circadian) rhythms in immune function may offer a lever to boost therapeutic success. Studies suggest that time of day influences immune-based therapies, including vaccines, hematopoietic stem cell transplantation, and checkpoint inhibitors for cancer. However, the clinical relevance of biological rhythms to CAR-T cell therapy remains unknown. Methods We retrospectively analyzed CAR-T cell survival and complications based on infusion time at two geographically distinct hospitals in St. Louis, Missouri (n=363), and Portland, Oregon (n=307) between 2018 and 2024. 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, adjusting for patient, oncological, and treatment characteristics. Findings Morning CAR-T cell infusions were associated with higher overall survival and lower rates of neurotoxicity before and after adjusting for confounders. Each hour earlier in the day that CAR-T cell treatment was given corresponded to a 22% increase in the odds of 90-day OS (adjusted odds ratio [aOR] 0·78, 95% CI 0·66–0·92, p=0·004). Simultaneously, for every hour CAR-T cell infusion was delayed, the adjusted odds of severe ICANS rose by 17% (aOR 1·17, 95% CI 1·01–1·34, p=0·031), and anakinra prescription rose by 26% (aOR 1·26, 95% CI 1·07–1·49, p=0·006). In contrast, we did not find an association between infusion time and severe CRS (aOR 0·96, 95% CI 0·74–1·23, p=0·73). Temporal patterns were most pronounced in women and patients receiving CD19-targeting CAR-T cell products for leukemia or lymphoma. Interpretation Time of day is a potent and easily modifiable factor that could optimize CAR-T cell clinical performance. Funding National Institutes of Health. Research in context Evidence before this study A review of PUBMED-cited articles shows that fundamental immune processes exhibit daily (circadian) rhythms in activity, leading immune-based therapies to vary in clinical efficacy based on the time of day. For example, the effectiveness of vaccines, checkpoint inhibitor therapy for cancer, and hematopoietic stem cell transplantation varies with the time of day they are administered to patients. One immunotherapy where dosing time remains unexplored in clinical data is CAR-T cells, a cell-based treatment for refractory B-cell cancers. Currently, the timing of CAR-T therapy is largely determined by staff availability. We hypothesized that CAR-T cell clinical safety and efficacy vary with administration time. If this hypothesis is correct, scheduling CAR-T cell infusions for specific times of day might improve the performance of this key treatment at minimal cost. Added value of this study This study reveals that the clinical performance of CAR-T cells varies substantially with administration time. It informs practice by showing that morning CAR-T cell infusions correlate with optimal therapeutic index based on better survival and less neurotoxicity. The study also identifies women and patients receiving anti-CD19 CAR-T cells as subgroups that may benefit the most from timed CAR-T cell infusions. Implications of all the available evidence This study on CAR-T cells should be understood in the context of growing evidence that circadian rhythms in immunity are broadly clinically translatable. The findings should prompt prospective trials that test time-of-day prioritization and, if validated, changes to CAR-T cell practice patterns. The findings also have implications for clinical trials applying CAR-T cells to new indications. Without controlling for time-of-treatment, diurnal rhythms in CAR-T cell effectiveness could be a significant confounder that could lead to false-negative or false-positive conclusions.