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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)285-295
Number of pages11
JournalCPT: Pharmacometrics and Systems Pharmacology
Volume8
Issue number5
DOIs
StatePublished - May 1 2019

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Antigens
Kinetics
Model-based
Cell- and Tissue-Based Therapy
Therapy
Cytokines
Half-Life
B Cells
Cell
Adrenal Cortex Hormones
B-Lymphocytes
Intrinsic Factor
Cells
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Mixed Effects Model
Pediatrics
Evaluate
Young Adult
Leukemia
Doubling

ASJC Scopus subject areas

  • Modeling and Simulation
  • Pharmacology (medical)

Cite this

Tisagenlecleucel Model-Based Cellular Kinetic Analysis of Chimeric Antigen Receptor–T Cells. / Stein, Andrew M.; Grupp, Stephan A.; Levine, John E.; Laetsch, Theodore W; Pulsipher, Michael A.; Boyer, Michael W.; August, Keith J.; Levine, Bruce L.; Tomassian, Lori; Shah, Sweta; Leung, Mimi; Huang, Pai Hsi; Awasthi, Rakesh; Mueller, Karen Thudium; Wood, Patricia A.; June, Carl H.

In: CPT: Pharmacometrics and Systems Pharmacology, Vol. 8, No. 5, 01.05.2019, p. 285-295.

Research output: Contribution to journalArticle

Stein, AM, Grupp, SA, Levine, JE, Laetsch, TW, Pulsipher, MA, Boyer, MW, August, KJ, Levine, BL, Tomassian, L, Shah, S, Leung, M, Huang, PH, Awasthi, R, Mueller, KT, Wood, PA & June, CH 2019, 'Tisagenlecleucel Model-Based Cellular Kinetic Analysis of Chimeric Antigen Receptor–T Cells', CPT: Pharmacometrics and Systems Pharmacology, vol. 8, no. 5, pp. 285-295. https://doi.org/10.1002/psp4.12388
Stein, Andrew M. ; Grupp, Stephan A. ; Levine, John E. ; Laetsch, Theodore W ; Pulsipher, Michael A. ; Boyer, Michael W. ; August, Keith J. ; Levine, Bruce L. ; Tomassian, Lori ; Shah, Sweta ; Leung, Mimi ; Huang, Pai Hsi ; Awasthi, Rakesh ; Mueller, Karen Thudium ; Wood, Patricia A. ; June, Carl H. / Tisagenlecleucel Model-Based Cellular Kinetic Analysis of Chimeric Antigen Receptor–T Cells. In: CPT: Pharmacometrics and Systems Pharmacology. 2019 ; Vol. 8, No. 5. pp. 285-295.
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