Efficacy of Blimp-1 KO CAR-T cells against multiple myeloma
Battram AM, Mañé Pujol J, Moreno DF, et al. Genetic Disruption of Blimp-1 Drastically Augments the Antitumor Efficacy of BCMA-Targeting CAR-T Cells. Blood Advances. 2024; (doi: 10.1182/bloodadvances.2024013209).
Researchers suspect that ablation of the transcription factor Blimp-1 might address the lack of durable efficacy observed with chimeric antigen receptor T-cells (CAR-T) targeting B-cell maturation antigen (BCMA) for multiple myeloma. While the treatment works, scientists believe the CAR-T cells differentiate too early, thwarting the formation of long-lived memory cells required to sustain anti-tumor activity. After using gene editing to ablate Blimp-1 expression, a mouse model of advanced multiple myeloma demonstrated that Blimp-1 knockout (KO) CAR-T cells slowed or prevented disease progression to a greater extent than control CAR-T cells. RNA-sequencing analysis revealed the presence of a memory-like transcriptomic signature that likely mediates improved effector function and increased energetic capacity in tumor-exposed Blimp-1 KO CAR-T cells. According to the authors, other potential factors that may contribute to the better performance of anti-BCMA CAR-T cells — and, therefore, that may represent therapeutic targets going forward — include repressed CAR-T cell dysfunction and enhanced ribosome biogenesis.