CTL019 Model-Based Cellular Kinetic Analysis of Chimeric Antigen Receptor (CAR) T Cells to Characterize the Impact of Tocilizumab on Expansion and to Identify Correlates of Cytokine Release Syndrome Severity

Background: CTL019 is an investigational therapy whereby autologous T cells are genetically engineered with a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant B cells. Data from two phase 2 studies (ELIANA; NCT02435849 and ENSIGN; NCT02228096) in pediatric and young adult relapsed/refractory (r/r) B-cell ALL were pooled to evaluate cellular kinetics of CTL019.

Aim: Evaluate the impact of clinically relevant intrinsic and extrinsic factors on CTL019 cellular kinetics and correlates for CRS severity using a mathematical model.

Methods: A cellular kinetic model was developed based on a previous analysis for quantifying T cell turnover [1] to characterize the CTL019 kinetics as measured by qPCR; the kinetics were described as having exponential growth, followed by a bi-exponential decline. The impact of tocilizumab and corticosteroids on CTL019 expansion rate was explored using covariate effects (F_toci, F_ster) on the expansion rate (ρ), as shown in Figure 1. The impact on peak concentration C_max by study, sex, race, Down syndrome, prior hematopoietic stem cell transplantation, fludarabine-based lymphodepletion therapy, CTL019 product transfection efficiency, tocilizumab, corticosteroids, and CTL019 dose were explored using a covariate model. The relationship between CRS severity and the model parameters C_max and t_max, from Figure 1 were also explored.

Results: Data from 90 pts (ELIANA, n=61; ENSIGN, n=29) were pooled for this analysis. The model-estimated C_max for patients receiving tocilizumab was 2-fold higher than those not receiving tocilizumab; this is consistent with the finding that there is 1.4-fold higher C_max in patients with G3/4 CRS (p=0.006). No impact of other intrinsic and extrinsic factors on C_max was identified. The Noncompartmental Analysis (NCA) showed that higher tumor burden at enrollment also correlated with greater C_max and increased CRS grade [2]. Tocilizumab and corticosteroids, dosed as defined in the protocol, were not observed to have an impact on the CTL019 expansion rate F_toci = 1.09 (0.81-1.26 90% Confidence Interval (CI)), and F_ster = 1 (0.85-1.31 90% CI). Three representative patient profiles (Figure 2) show continued CTL019 expansion after tocilizumab and corticosteroids. Thus, no evidence that tocilizumab reduces CTL019 expansion has been observed.

Conclusion: Pts with r/r ALL with higher peak transgene levels were more likely to develop Grade 3 and 4 CRS based upon both NCA and modeling of cellular kinetics; these patients were more likely to receive anti-cytokine therapy, such as tocilizumab, resulting in the higher Cmax among patients receiving tocilizumab. This work represents the first model-based analysis of a CAR T cell therapy; the model based analysis was used to assess the factors impacting C_max and showed that there was no evidence that tocilizumab impacted the rate of expansion

References:

1. De Boer RJ, Perelson, AS. Quantifying T lymphocyte turnover. Journal of Theoretical Biology, 327, 45-87, 2013.

2. Mueller, KT, et al. Cellular Kinetics of Chimeric Antigen Receptor T Cells (CTL019) in Patients with Relapsed/Refractory CD19+ Leukemia. Blood, 2016: 128:220.

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