https://orcid.org/0000-0002-0379-5297
Key Points
Bacteroides fragilis and inosine biosynthesis are key CAR T-cell response biomarkers, supporting microbiome-based strategies for treatment.
CAR T-cell adverse events were linked to specific microbes and serum fatty acids, with higher acetate/butyrate in patients without AEs.
CD19 CAR T-cell therapy has revolutionized treatment for relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL), but challenges like post-treatment failure and immune-related adverse events (AEs) persist. This study explores the gut microbiome as a predictive biomarker for CAR T-cell therapy outcomes and toxicity. Stool and serum samples from RR-DLBCL patients were analyzed at apheresis (47 samples) and one month post-infusion (32 samples) using whole-genome sequencing metagenomics. When compared with healthy controls and newly diagnosed DLBCL, RR-DLBCL showed significant gut dysbiosis, characterized by increased Proteobacteria and Enterobacteriaceae. Responders to treatment had higher levels of Bacteroides fragilis, while non-responders exhibited higher levels of Faecalibacterium prausnitzii. Functional metagenomic analysis suggested enrichment of inosine biosynthesis pathways in responders, and elevated serum inosine demonstrated an exploratory association with improved progression-free survival. Distinct microbial taxa and serum fatty acid profiles were also linked to CAR T-cell-related AEs, with higher acetate and butyrate levels in patients without AEs, and increased isovalerate in those with AEs. These findings indicate that gut microbiome features-particularly Bacteroides fragilis and inosine metabolism-may serve as candidate biomarkers for CAR T-cell therapy outcomes and toxicity. However, given the exploratory nature of these analyses and the limited cohort size, results should be interpreted cautiously. Larger, prospective studies will be required to validate these observations and to assess the potential of microbiome-based strategies to optimize CAR T-cell therapy in RR-DLBCL.
