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Accelerating clinical-scale production of BCMA CAR T cells with defined maturation stages

The advent of CAR T cells targeting CD19 or BCMA on B cell neoplasm demonstrated remarkable efficacy, but rapid relapses and primary refractoriness remains challenging. A leading cause of CAR T cell failure is their lack of expansion and limited persistence. Long-lived, self-renewing multipotent T m...

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Autores principales: Joedicke, Jara J., Großkinsky, Ulrich, Gerlach, Kerstin, Künkele, Annette, Höpken, Uta E., Rehm, Armin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8791860/
https://www.ncbi.nlm.nih.gov/pubmed/35118163
http://dx.doi.org/10.1016/j.omtm.2021.12.005
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author Joedicke, Jara J.
Großkinsky, Ulrich
Gerlach, Kerstin
Künkele, Annette
Höpken, Uta E.
Rehm, Armin
author_facet Joedicke, Jara J.
Großkinsky, Ulrich
Gerlach, Kerstin
Künkele, Annette
Höpken, Uta E.
Rehm, Armin
author_sort Joedicke, Jara J.
collection PubMed
description The advent of CAR T cells targeting CD19 or BCMA on B cell neoplasm demonstrated remarkable efficacy, but rapid relapses and primary refractoriness remains challenging. A leading cause of CAR T cell failure is their lack of expansion and limited persistence. Long-lived, self-renewing multipotent T memory stem cells (T(SCM)) and T central memory cells (T(CM)) likely sustain superior tumor regression, but their low frequencies in blood from cancer patients impose a major hurdle for clinical CAR T production. We designed a clinically compliant protocol for generating BCMA CAR T cells starting with increased T(SCM)/T(CM) cell input. A CliniMACS Prodigy process was combined with flow cytometry-based enrichment of CD62L(+)CD95(+) T cells. Although starting with only 15% of standard T cell input, the selected T(SCM)/T(CM) material was efficiently activated and transduced with a BCMA CAR-encoding retrovirus. Cultivation in the presence of IL-7/IL-15 enabled the harvest of CAR T cells containing an increased CD4(+) T(SCM) fraction and 70% T(SCM) cells amongst CD8(+). Strong cell proliferation yielded cell numbers sufficient for clinical application, while effector functions were maintained. Together, adaptation of a standard CliniMACS Prodigy protocol to low input numbers resulted in efficient retroviral transduction with a high CAR T cell yield.
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spelling pubmed-87918602022-02-02 Accelerating clinical-scale production of BCMA CAR T cells with defined maturation stages Joedicke, Jara J. Großkinsky, Ulrich Gerlach, Kerstin Künkele, Annette Höpken, Uta E. Rehm, Armin Mol Ther Methods Clin Dev Original Article The advent of CAR T cells targeting CD19 or BCMA on B cell neoplasm demonstrated remarkable efficacy, but rapid relapses and primary refractoriness remains challenging. A leading cause of CAR T cell failure is their lack of expansion and limited persistence. Long-lived, self-renewing multipotent T memory stem cells (T(SCM)) and T central memory cells (T(CM)) likely sustain superior tumor regression, but their low frequencies in blood from cancer patients impose a major hurdle for clinical CAR T production. We designed a clinically compliant protocol for generating BCMA CAR T cells starting with increased T(SCM)/T(CM) cell input. A CliniMACS Prodigy process was combined with flow cytometry-based enrichment of CD62L(+)CD95(+) T cells. Although starting with only 15% of standard T cell input, the selected T(SCM)/T(CM) material was efficiently activated and transduced with a BCMA CAR-encoding retrovirus. Cultivation in the presence of IL-7/IL-15 enabled the harvest of CAR T cells containing an increased CD4(+) T(SCM) fraction and 70% T(SCM) cells amongst CD8(+). Strong cell proliferation yielded cell numbers sufficient for clinical application, while effector functions were maintained. Together, adaptation of a standard CliniMACS Prodigy protocol to low input numbers resulted in efficient retroviral transduction with a high CAR T cell yield. American Society of Gene & Cell Therapy 2021-12-25 /pmc/articles/PMC8791860/ /pubmed/35118163 http://dx.doi.org/10.1016/j.omtm.2021.12.005 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Joedicke, Jara J.
Großkinsky, Ulrich
Gerlach, Kerstin
Künkele, Annette
Höpken, Uta E.
Rehm, Armin
Accelerating clinical-scale production of BCMA CAR T cells with defined maturation stages
title Accelerating clinical-scale production of BCMA CAR T cells with defined maturation stages
title_full Accelerating clinical-scale production of BCMA CAR T cells with defined maturation stages
title_fullStr Accelerating clinical-scale production of BCMA CAR T cells with defined maturation stages
title_full_unstemmed Accelerating clinical-scale production of BCMA CAR T cells with defined maturation stages
title_short Accelerating clinical-scale production of BCMA CAR T cells with defined maturation stages
title_sort accelerating clinical-scale production of bcma car t cells with defined maturation stages
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8791860/
https://www.ncbi.nlm.nih.gov/pubmed/35118163
http://dx.doi.org/10.1016/j.omtm.2021.12.005
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