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Population Cellular Kinetics of Lisocabtagene Maraleucel, an Autologous CD19-Directed Chimeric Antigen Receptor T-Cell Product, in Patients with Relapsed/Refractory Large B-Cell Lymphoma
BACKGROUND AND OBJECTIVES: Lisocabtagene maraleucel (liso-cel) is a CD19-directed, defined composition, 4-1BB chimeric antigen receptor (CAR) T-cell product administered at equal target doses of CD8(+) and CD4(+) CAR(+) T cells. Large between-subject variability has been noted with CAR T-cell therap...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8613160/ https://www.ncbi.nlm.nih.gov/pubmed/34125421 http://dx.doi.org/10.1007/s40262-021-01039-5 |
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author | Ogasawara, Ken Dodds, Michael Mack, Timothy Lymp, James Dell’Aringa, Justine Smith, Jeff |
author_facet | Ogasawara, Ken Dodds, Michael Mack, Timothy Lymp, James Dell’Aringa, Justine Smith, Jeff |
author_sort | Ogasawara, Ken |
collection | PubMed |
description | BACKGROUND AND OBJECTIVES: Lisocabtagene maraleucel (liso-cel) is a CD19-directed, defined composition, 4-1BB chimeric antigen receptor (CAR) T-cell product administered at equal target doses of CD8(+) and CD4(+) CAR(+) T cells. Large between-subject variability has been noted with CAR T-cell therapies; patient characteristics might contribute to CAR T-cell expansion variability. We developed a population cellular kinetic model to characterize the kinetics of the liso-cel transgene, via quantitative polymerase chain reaction assessment after intravenous infusion of liso-cel, and to understand covariates that might influence liso-cel kinetics in individual patients. METHODS: We employed nonlinear mixed-effects modeling to develop a population cellular kinetic model for liso-cel. The population cellular kinetic analysis was performed using 2524 post-infusion transgene observations from 261 patients with relapsed/refractory large B-cell lymphoma who were treated with a single dose of liso-cel in TRANSCEND NHL 001. Covariates for the analysis included baseline intrinsic factors such as age, baseline disease characteristics, and liso-cel and coadministration factors. RESULTS: Liso-cel cellular kinetics were well described by a piecewise model of cellular growth kinetics that featured lag, exponential growth, and biexponential decay phases. Population means (95% confidence interval) of lag phase duration, doubling time, time to maximum levels, initial decline half-life, and terminal half-life were 3.27 (2.71–3.97), 0.755 (0.667–0.821), 9.29 (8.81–9.70), 5.00 (4.15–5.90), and 352 (241–647) days, respectively. The magnitude of effect on liso-cel expansion metrics demonstrated that the covariate associations were smaller than the residual between-subject variability in the population. CONCLUSIONS: The covariates tested were not considered to have a meaningful impact on liso-cel kinetics. CLINICAL TRIAL REGISTRATION: NCT02631044. |
format | Online Article Text |
id | pubmed-8613160 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-86131602021-12-10 Population Cellular Kinetics of Lisocabtagene Maraleucel, an Autologous CD19-Directed Chimeric Antigen Receptor T-Cell Product, in Patients with Relapsed/Refractory Large B-Cell Lymphoma Ogasawara, Ken Dodds, Michael Mack, Timothy Lymp, James Dell’Aringa, Justine Smith, Jeff Clin Pharmacokinet Original Research Article BACKGROUND AND OBJECTIVES: Lisocabtagene maraleucel (liso-cel) is a CD19-directed, defined composition, 4-1BB chimeric antigen receptor (CAR) T-cell product administered at equal target doses of CD8(+) and CD4(+) CAR(+) T cells. Large between-subject variability has been noted with CAR T-cell therapies; patient characteristics might contribute to CAR T-cell expansion variability. We developed a population cellular kinetic model to characterize the kinetics of the liso-cel transgene, via quantitative polymerase chain reaction assessment after intravenous infusion of liso-cel, and to understand covariates that might influence liso-cel kinetics in individual patients. METHODS: We employed nonlinear mixed-effects modeling to develop a population cellular kinetic model for liso-cel. The population cellular kinetic analysis was performed using 2524 post-infusion transgene observations from 261 patients with relapsed/refractory large B-cell lymphoma who were treated with a single dose of liso-cel in TRANSCEND NHL 001. Covariates for the analysis included baseline intrinsic factors such as age, baseline disease characteristics, and liso-cel and coadministration factors. RESULTS: Liso-cel cellular kinetics were well described by a piecewise model of cellular growth kinetics that featured lag, exponential growth, and biexponential decay phases. Population means (95% confidence interval) of lag phase duration, doubling time, time to maximum levels, initial decline half-life, and terminal half-life were 3.27 (2.71–3.97), 0.755 (0.667–0.821), 9.29 (8.81–9.70), 5.00 (4.15–5.90), and 352 (241–647) days, respectively. The magnitude of effect on liso-cel expansion metrics demonstrated that the covariate associations were smaller than the residual between-subject variability in the population. CONCLUSIONS: The covariates tested were not considered to have a meaningful impact on liso-cel kinetics. CLINICAL TRIAL REGISTRATION: NCT02631044. Springer International Publishing 2021-06-14 2021 /pmc/articles/PMC8613160/ /pubmed/34125421 http://dx.doi.org/10.1007/s40262-021-01039-5 Text en © The Author(s) 2021, corrected publication 2021 https://creativecommons.org/licenses/by-nc/4.0/Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Original Research Article Ogasawara, Ken Dodds, Michael Mack, Timothy Lymp, James Dell’Aringa, Justine Smith, Jeff Population Cellular Kinetics of Lisocabtagene Maraleucel, an Autologous CD19-Directed Chimeric Antigen Receptor T-Cell Product, in Patients with Relapsed/Refractory Large B-Cell Lymphoma |
title | Population Cellular Kinetics of Lisocabtagene Maraleucel, an Autologous CD19-Directed Chimeric Antigen Receptor T-Cell Product, in Patients with Relapsed/Refractory Large B-Cell Lymphoma |
title_full | Population Cellular Kinetics of Lisocabtagene Maraleucel, an Autologous CD19-Directed Chimeric Antigen Receptor T-Cell Product, in Patients with Relapsed/Refractory Large B-Cell Lymphoma |
title_fullStr | Population Cellular Kinetics of Lisocabtagene Maraleucel, an Autologous CD19-Directed Chimeric Antigen Receptor T-Cell Product, in Patients with Relapsed/Refractory Large B-Cell Lymphoma |
title_full_unstemmed | Population Cellular Kinetics of Lisocabtagene Maraleucel, an Autologous CD19-Directed Chimeric Antigen Receptor T-Cell Product, in Patients with Relapsed/Refractory Large B-Cell Lymphoma |
title_short | Population Cellular Kinetics of Lisocabtagene Maraleucel, an Autologous CD19-Directed Chimeric Antigen Receptor T-Cell Product, in Patients with Relapsed/Refractory Large B-Cell Lymphoma |
title_sort | population cellular kinetics of lisocabtagene maraleucel, an autologous cd19-directed chimeric antigen receptor t-cell product, in patients with relapsed/refractory large b-cell lymphoma |
topic | Original Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8613160/ https://www.ncbi.nlm.nih.gov/pubmed/34125421 http://dx.doi.org/10.1007/s40262-021-01039-5 |
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