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

ABSTRACT: 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 (TSCM) and T central memory cells (TCM) 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 TSCM/TCM 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 TSCM/TCM 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+ TSCM fraction and 70% TSCM 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. Graphical Abstract CAR T cell therapies can fail when these cells disappear. Rehm and colleagues demonstrate a procedure for T memory stem cell-enrichment (TSCM) using FACS combined with bioreactor expansion. Despite low TSCM frequencies in patients, this technology is suitable for providing clinical scale BCMA CAR T cells, facilitating extended persistence and tumor control.

SUBMITTER: Joedicke J

PROVIDER: S-EPMC8791860 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:This SuperSeries is composed of the SubSeries listed below.

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