Model‐Based Cellular Kinetic Analysis of Chimeric Antigen Receptor‐T Cells in Humans

Chimeric antigen receptor (CAR)‐T cell therapy has achieved considerable success in treating B‐cell hematologic malignancies. However, the challenges of extending CAR‐T therapy to other tumor types, particularly solid tumors, remain appreciable. There are substantial variabilities in CAR‐T cellular kinetics across CAR‐designs, CAR‐T products, dosing regimens, patient responses, disease types, tumor burdens, and lymphodepletion conditions. As a “living drug,” CAR‐T cellular kinetics typically exhibit four distinct phases: distribution, expansion, contraction, and persistence. The cellular kinetics of CAR‐T may correlate with patient responses, but which factors determine CAR‐T cellular kinetics remain poorly defined. Herein, we developed a cellular kinetic model to retrospectively characterize CAR‐T kinetics in 217 patients from 7 trials and compared CAR‐T kinetics across response status, patient populations, and tumor types. Based on our analysis results, CAR‐T cells exhibited a significantly higher cell proliferation rate and capacity but a lower contraction rate in patients who responded to treatment. CAR‐T cells proliferate to a higher degree in hematologic malignancies than in solid tumors. Within the assessed dose ranges (10 7 ‒10 9 cells), CAR‐T doses were weakly correlated with CAR‐T cellular kinetics and patient response status. In conclusion, the developed CAR‐T cellular kinetic model adequately characterized the multiphasic CAR‐T cellular kinetics and supported systematic evaluations of the potential influencing factors, which can have significant implications for the development of more effective CAR‐T therapies.