菌群塑造 CAR-T 治疗的代谢与免疫决定因素并与骨髓瘤结局相关

UNLABELLED: Multiple myeloma remains incurable despite advances in immunotherapies like chimeric antigen receptor (CAR) T-cell therapy.

This study investigates the role of metabolites and gut microbiota in clinical outcomes in patients treated with the humanized B-cell maturation antigen (BCMA)-directed CAR-T therapy ARI0002h. Stool metabolites, particularly succinate, were associated with CAR T-cell phenotypes and persistence in patients.

In CAR T-cell culture, succinate supplementation enhanced CD4+ central memory phenotype and respiratory capacity. In a murine myeloma model, a succinate-enhancing diet significantly improved CAR T-cell persistence and showed a trend toward better tumor control.

Furthermore, Acidaminococcaceae, Monoglobaceae, or Akkermansiaceae, along with specific metabolites, were associated with CAR T-cell clinical outcomes. These multimodal profiles were integrated into response models, including one that identified patients likely to achieve a complete response by days 100 and 180 after infusion.

These findings suggest that metabolites and gut microbiota correlate with CAR T-cell therapy responses and can be a valuable tool for risk assessment. SIGNIFICANCE: This study integrates microbial profiles into response models, providing a tool to identify patients with multiple myeloma who may benefit from BCMA-directed CAR T-cell therapy optimization by identifying bacterial taxa and metabolites associated with CAR T-cell persistence and therapeutic outcomes.