Population cellular kinetics and exposure-CSR analysis of CAR-T cells in Chinese patients with relapsed/refractory B-ALL

Background CD19-targeting chimeric antigen receptor (CAR)-T cells have demonstrated great efficacy in treating relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL). Despite the high objective response rate of CAR-T cell therapy, high-risk adverse event of cytokine-release syndrome occur unexpectedly. Objective As living gene-modified cells, CAR-T cells exhibit unique kinetics. This study aimed to explore the relationship between CAR-T therapy-related CRS and the kinetics of CAR-T cells. Methods In this study, data for 2184 CAR-transgene copies from 131 B-ALL patients treated with IL-6 knockdown CD19-targeting CAR-T cells were included to characterize the cellular kinetics using a nonlinear mixed-effects (NLME) model. The extrinsic and intrinsic factors that may impact the kinetics of CAR-T cells were also evaluated. Results The CD4 + /CD8 + ratio of CAR-T cell products was shown to be significantly positively correlated with T max , suggesting that a higher CD4 + /CD8 + ratio may lead to a delay in reaching the maximum expansion, while other candidate covariates including tumor burden, CAR-T doses and comedication were not significantly associated with the kinetics of CAR-T cells. The estimated values of the cellular kinetic parameters C max , T max and Fold x were 4.696 × 10 4 copies/μg, 13.0 days, and 127.5, respectively. The estimated AUC 0-28d and AUC 0-90d accounted for only 13.0% and 18.5% of AUC 0-inf , respectively, indicating that there was long-term persistence of memory CAR-T cells in vivo . In addition, the incidence of CRS was investigated to be correlated with the early kinetics of CAR-T cells, and the optimal cutoff values of C max and AUC 0-28d for severe CRS were 6.951 × 10 4 copies/μg and 4.962 × 10 5 copies/μg × days, respectively.