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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

Andrew M Stein, Stephan A Grupp, John E Levine, Theodore W Laetsch, Michael A Pulsipher, Michael W Boyer, Keith J August, Bruce L Levine, Carl H June, Lori Tomassian, Sweta Shah, Mimi Leung, Pai-Hsi Huang, Sebastien Jolivet, Rakesh Awasthi, Karen Thudium Mueller, Patricia A Wood and Shannon L Maude

Abstract

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 (Ftoci, Fster) on the expansion rate (ρ), as shown in Figure 1. The impact on peak concentration Cmax 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 Cmax and tmax, 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 Cmax 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 Cmax in patients with G3/4 CRS (p=0.006). No impact of other intrinsic and extrinsic factors on Cmax was identified. The Noncompartmental Analysis (NCA) showed that higher tumor burden at enrollment also correlated with greater Cmax 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 Ftoci = 1.09 (0.81-1.26 90% Confidence Interval (CI)), and Fster = 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 Cmax 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.

Disclosures Stein: Novartis Instutitute for BioMedical Research: Employment. Grupp: Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties; Jazz Pharmaceuticals: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Other: grant. Levine: Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Laetsch: Novartis Pharmaceuticals Corporation: Consultancy. Pulsipher: Adaptive: Other: Advisory board 6/17; CSL Behring: Other: advisory board Feb 2017; Jazz Pharmaceuticals: Other: advisory board, education; Chimerix: Other: Advisory board Dec 2015; Novartis Pharmaceuticals Corporation: Consultancy, Other: Phase II steering committee. Boyer: Novartis Pharmaceuticals Corporation: Honoraria. August: Novartis Pharmaceuticals Corporation: Consultancy. Levine: Brammer Bio: Consultancy; Novartis Pharmaceuticals Corporation: Patents & Royalties, Research Funding; GE Healthcare: Consultancy; Tmunity Therapeutics: Equity Ownership, Research Funding. June: Immune Design: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; WIRB/Copernicus Group: Honoraria, Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership, Research Funding; Novartis: Patents & Royalties, Research Funding; Celldex: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tomassian: Novartis Pharmaceuticals Corporation: Employment. Shah: Novartis Pharmaceuticals Corporation: Employment. Leung: Novartis Pharmaceuticals Corporation: Employment. Huang: Novartis Pharmaceuticals Corporation: Employment. Jolivet: Novartis Pharma AG: Employment. Awasthi: Novartis Pharmaceuticals Corporation: Employment. Mueller: Novartis Pharmaceuticals Corporation: Employment. Wood: Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Maude: Novartis Pharmaceuticals: Consultancy, Other: Medical Advisory Boards.

  • * Asterisk with author names denotes non-ASH members.