Longitudinal analysis of gut microbiome and metabolome correlates of response and toxicity with idecabtagene vicleucel.

Abstract

Increasing evidence suggests that the gut microbiome may influence the responses and toxicities associated with chimeric antigen receptor (CAR) therapy. We conducted whole-genome shotgun sequencing on stool samples (n=117) collected at various times from multiple myeloma patients (n=33) undergoing idecabtagene vicleucel (ide-cel) anti-B cell maturation antigen CAR-T therapy. We observed a significant decrease in bacterial diversity post-ide-cel infusion, along with significant differences in bacterial composition linked to therapy response and toxicities. Specifically, we found significant enrichment of Flavonifractor plautii, Bacteroides thetaiotaomicron, Blautia fecis, and Dysosmobacter species in ide-cel responders. A notable finding was the link between major microbiome disruption, defined as dominant specific taxa (greater than 35% prevalence) and increased facultative pathobionts like Enterococcus, with ide-cel toxicities, especially cytokine release syndrome (CRS). Patients with genus dominance in baseline samples had a higher incidence of grade 2 or higher CRS at 46.2% compared to those without genus dominance (11.1%, p=0.043). Additionally, network analysis and mass spectrometric assessment of stool metabolites revealed important associations and pathways, such as Flavonifractor plautii being linked to increased indole metabolites and pathways in responders. Our findings uncover novel microbiome associations between ide-cel responses and toxicities that may be useful for developing modalities to improve CAR-T outcomes.