Axicabtagene ciloleucel (axi-cel), a CAR-T cell therapy for relapsed and refractory non-Hodgkin’s lymphoma (NHL), demonstrates substantial inter-individual variability in cellular kinetics. This variability complicates predicting therapeutic outcomes and managing associated toxicities, such as cytokine release syndrome (CRS) and neurological events (NEs). Identifying factors that influence CAR-T kinetics is critical for optimizing treatment and improving patient care.
Study Highlights:
- Kinetic Modeling:
- A piecewise model described axi-cel kinetics, featuring a rapid expansion phase followed by a triexponential decline, including long-term persistence.
- Over 400 patients from three clinical trials (ZUMA-1, ZUMA-5, ZUMA-7) were analyzed, with 2050 transgene observations contributing to the model.
- Covariate Analysis:
- Despite assessing a broad range of covariates—including patient characteristics, product attributes, disease type, and tumor burden—none substantially influenced axi-cel exposure metrics like peak concentration or long-term persistence.
- In vitro doubling time during manufacturing and total T-cell dose infused affected the growth phase duration but did not predict exposure variability.
- Higher peak concentrations were linked to reactive use of tocilizumab or corticosteroids for managing toxicities.
- Clinical Implications:
- Current covariates fail to fully explain the observed variability in axi-cel kinetics, highlighting the need for further research.
- Future studies should explore additional biological or mechanistic factors to better understand CAR-T dynamics and establish dose–exposure relationships.
Conclusion:
This study sheds light on the challenges of modeling CAR-T kinetics and underscores the importance of continued investigation to refine therapeutic strategies for axi-cel and other CAR-T cell therapies.
