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

Area of Science:

• Immunotherapy
• Cellular Therapy
• Oncology

Background:

• CAR T-cell therapy shows promise for B cell neoplasms but faces challenges like relapse and limited persistence.
• CAR T-cell failure is often due to insufficient expansion and persistence.
• Long-lived T memory stem cells (T_SCM) and T central memory cells (T_CM) are crucial for sustained tumor regression but are scarce in patient samples.

Purpose of the Study:

• To develop a clinically compliant protocol for generating BCMA CAR T-cells with enhanced T_SCM and T_CM cell input.
• To overcome the hurdle of low T_SCM/T_CM frequencies in patient-derived T-cells for CAR T production.

Main Methods:

• A CliniMACS Prodigy process was combined with flow cytometry to enrich for CD62L+CD95+ T-cells (T_SCM/T_CM).
• Selected T_SCM/T_CM cells were activated and transduced with a BCMA CAR-encoding retrovirus.
• Cells were cultured with IL-7/IL-15 to promote expansion and persistence.

Main Results:

• Efficient activation and retroviral transduction were achieved even with reduced T-cell input (15% of standard).
• The harvested CAR T-cells showed an increased CD4+ T_SCM fraction and 70% T_SCM cells among CD8+ T-cells.
• Sufficient cell numbers for clinical application were obtained with maintained effector functions.

Conclusions:

• Adapting a standard CliniMACS Prodigy protocol for low T_SCM/T_CM input enables efficient retroviral transduction.
• This optimized protocol results in a high yield of CAR T-cells with a favorable memory phenotype, addressing key limitations in CAR T-cell therapy.