Longitudinal analysis of gut microbiome and metabolome correlates of response and toxicity with idecabtagene vicleucel
Increasing evidence suggests that the gut microbiome may influence the responses and toxicities associated with chimeric antigen receptor T-cell (CAR-T) therapy. We conducted whole-genome shotgun sequencing on stool samples (N = 117) collected at various times from patients with multiple myeloma (n = 33) who underwent idecabtagene vicleucel (ide-cel) anti-B-cell maturation antigen CAR-T therapy. We observed a significant decrease in bacterial diversity after ide-cel infusion, along with significant differences in the 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 of major microbiome disruption, defined as the presence of dominant specific taxa (>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% than those without genus dominance (11.1%; P = .043). In addition, network analysis and mass spectrometric assessment of stool metabolites revealed important associations and pathways, such as F plautii being linked to increased indole metabolites and pathways in responders. Our findings uncovered novel microbiome associations between ide-cel responses and toxicities that may be useful for developing modalities to improve CAR-T outcomes.
Authors
- Melody Becnel (ORCID: https://orcid.org/0000-0001-6295-5433)
- Mahmoud Gaballa (ORCID: https://orcid.org/0000-0002-3928-6590)
- Michael David Jain (ORCID: https://orcid.org/0000-0002-7789-1257)
- Sheeba K. Thomas (ORCID: https://orcid.org/0000-0001-8596-7058)
- Salvatore Corallo (ORCID: https://orcid.org/0009-0001-2450-4022)
- Lubna Rehman (ORCID: https://orcid.org/0000-0002-5832-6578)
- Frederick Lundry Locke (ORCID: https://orcid.org/0000-0001-9063-6691)
- Faezeh Darbaniyan
- Robert R. Jenq (ORCID: https://orcid.org/0000-0002-5434-439X)
- Neeraj Y. Saini (ORCID: https://orcid.org/0000-0001-7435-0933)
- Mark R. Tanner (ORCID: https://orcid.org/0000-0002-6516-0166)
- Robert Zygmunt Orlowski (ORCID: https://orcid.org/0000-0002-5723-4129)
- Marco L. Davila (ORCID: https://orcid.org/0000-0002-6270-3065)
- Satabdi Saha (ORCID: https://orcid.org/0000-0002-0117-9431)
- Hans Chulhee Lee (ORCID: https://orcid.org/0000-0001-8545-3292)
- Reetakshi Arora (ORCID: https://orcid.org/0000-0002-5437-4521)
- Krina K. Patel (ORCID: https://orcid.org/0000-0002-8894-027X)
- Sattva Swarup Neelapu (ORCID: https://orcid.org/0000-0003-1045-4914)
- Meghan Menges (ORCID: https://orcid.org/0009-0007-7446-9492)
- Chia‐Chi Chang (ORCID: https://orcid.org/0000-0003-0050-1705)
- Christopher R. Flowers (ORCID: https://orcid.org/0000-0002-9524-3990)
- Christine B. Peterson (ORCID: https://orcid.org/0000-0003-3316-0468)
- Abdur Rehman (ORCID: https://orcid.org/0000-0003-3785-2007)
- Doris K. Hansen
- Elizabeth J. Shpall
- Donna M. Weber
Institutions
- Roswell Park Comprehensive Cancer Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of South Florida (US)
- Moffitt Cancer Center (US)
Publication Details
- Journal
- Blood Advances
- Published
- 2025-04-08
- DOI
- https://doi.org/10.1182/bloodadvances.2024014476
- Citations
- 6
- Primary Topic
- Mycobacterium research and diagnosis
- Type
- article
- Field-Weighted Citation Impact
- 8.13
Funders
- Gilead Sciences
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Moffitt Cancer Center
- Incyte
- National Institutes of Health
- University of Texas MD Anderson Cancer Center
- National Cancer Institute