Tisagenlecleucel Model-Based Cellular Kinetic Analysis of Chimeric Antigen Receptor-T Cells

Abstract

Tisagenlecleucel is a chimeric antigen receptor-T cell therapy that facilitates the killing of CD19⁺ B cells. A model was developed for the kinetics of tisagenlecleucel and the impact of therapies for treating cytokine release syndrome (tocilizumab and corticosteroids) on expansion. Data from two phase II studies in pediatric and young adult relapsed/refractory B cell acute lymphoblastic leukemia were pooled to evaluate this model and evaluate extrinsic and intrinsic factors that may impact the extent of tisagenlecleucel expansion. The doubling time, initial decline half-life, and terminal half-life for tisagenlecleucel were 0.78, 4.3, and 220 days, respectively. No impact of tocilizumab or corticosteroids on the expansion rate was observed. This work represents the first mixed-effect model-based analysis of chimeric antigen receptor-T cell therapy and may be clinically impactful as future studies examine prophylactic interventions in patients at risk of higher grade cytokine release syndrome and the effects of these interventions on chimeric antigen receptor-T cell expansion.

Figure 1

Graphical representation of the cellular kinetic models. (a) The graph depicts the mathematical model of tisagenlecleucel following expansion at a rate (ρ) up to time to maximal expansion (T _max), followed by a biphasic contraction at rates α and β. Because F _B is much <1, the initial decline rate is well estimated by α. (b) Mathematical model for tisagenlecleucel expansion concurrent with tocilizumab and corticosteroid administration given at times T _toci and T _ster, respectively. The model allows for a reduced rate of expansion with F _ster, effect of steroids, and F _toci, effect of tocilizumab. F _B, fraction of transgene copies present during the decline at the gradual rate β, starting from T _max; F _ster, effect of steroids; F _toci, effect of tocilizumab; T _ster, time to maximal expansion with steroid therapy; T _toci, time to maximal expansion with tocilizumab therapy.

Figure 2

Compartmental model describing T‐cell kinetics. The model has exponential growth of effector cells (E) at rate ρ before time to maximal expansion (T _max). After T _max, effector cells rapidly decline at rate (α‐k) and convert to memory cells at rate k; the memory cells then decline at a rate β. The rapid decline is most likely caused by programmed cell death following immune activation, and a slower decline rate is indicative of a longer persistence of the memory effector T‐cell phenotype. The equations describing the rates of expansion and decline are shown. Additional information about the model can also be found in the Supplementary Material . C _max, maximal concentration; F _B, fraction of transgene copies present during the decline at the gradual rate β, starting from T _max; fold_x, fold expansion; F _ster, effect of steroids; F _toci, effect of tocilizumab; T _ster, time to maximal expansion with steroid therapy; T _toci, time to maximal expansion with tocilizumab therapy.

Figure 3

Model fits. (a) Visual predictive check of the model simulation compared with the data. The blue dots show the transgene copies per μg of genomic DNA, and the red asterisks denote simulated data points for the measurements that were below the limit of quantification (BLQ) of 50 transgene copies per μg. The blue lines show the 10th, 50th, and 90th percentiles calculated directly from the population data; the blue‐shaded areas denote the confidence intervals of the 10th and 90th percentiles from the model; and the pink shaded area shows the 50th percentile. The empirical percentiles lie within the confidence intervals, except at day 5, indicating that overall the model describes the data well. (b) Individual fits for tisagenlecleucel transgene copies per μg of genomic DNA (y‐axis) over time in months from CAR‐T cell infusion (x‐axis) observed in a representative set of patients. CAR, chimeric antigen receptor qPCR, quantitative polymerase chain reaction.

Figure 4

Individual fits for a subset of all patients with rich quantitative polymerase chain reaction (qPCR) sampling who received tocilizumab and/or corticosteroids. The red dashed lines indicate treatment with corticosteroids, and the green lines indicate treatment with tocilizumab. Each dot represents a measurable qPCR value. Black horizontal lines indicate the limit of quantification equal to 50 transgene copies per μg of genomic DNA. BLQ, below the limit of quantification.