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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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Detalles Bibliográficos
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
Descripción
Sumario: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.