Microbiota shape metabolic and immune determinants of CAR-T therapy and correlate with outcomes in myeloma

Abstract Multiple myeloma remains incurable despite advances in immunotherapies like CAR-T cell therapy. This study investigates the role of metabolites and gut microbiota in clinical outcomes in patients treated with the humanized 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 day 100 and 180 post-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.