Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Sep 3;6(5):484-504.
doi: 10.1158/2643-3230.BCD-24-0203.

Microbiota Shape Metabolic and Immune Determinants of CAR-T Therapy and Correlate with Outcomes in Myeloma

Mireia Uribe-Herranz  1   2 , Aina Oliver-Caldés  1   3 , Neus Martínez-Micaelo  4 , Marta Español-Rego  2 , Maria Val-Casals  1   5 , Roberto Martínez-Soler  1 , Elisa Rubio-Garcia  6   7   8   9 , Valeria Brunello  1 , Erik Z Mihelic  1 , Nela Klein-González  1   2   5 , Daniel Benítez-Ribas  2 , Núria Amigó  4   10   11 , Andrea Vergara  6   7   9   12 , Valentin Ortiz-Maldonado  3 , Luis Gerardo Rodríguez-Lobato  1   3 , Julio Delgado  3 , Iñaki Ortiz de Landazuri  1   2 , Verónica González-Calle  13 , Valentín Cabañas  14 , Beatriz Martin-Antonio  15 , Lorena Pérez-Amill  1   5 , Juan Luis Reguera-Ortega  16 , Paula Rodríguez-Otero  17 , Bruno Paiva  17 , Joaquín Martínez-López  18 , Maria-Victoria Mateos  13 , Mariona Pascal  1   2 , Álvaro Urbano-Ispizua  1   3 , Europa Azucena González-Navarro  2 , Carlos Fernández de Larrea  1   3 , Manel Juan  1   2   19   20
Affiliations

Microbiota Shape Metabolic and Immune Determinants of CAR-T Therapy and Correlate with Outcomes in Myeloma

Mireia Uribe-Herranz et al. Blood Cancer Discov. .

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

M. Val-Casals reports other support from Gyala Therapeutics S.L. outside the submitted work. V. Ortiz-Maldonado reports personal fees from Pfizer and Bristol Myers Squibb and other support from Kite Pharma outside the submitted work. L.G. Rodríguez-Lobato reports grants and personal fees from Johnson & Johnson, Amgen, GSK, Bristol Myers Squibb, Sanofi, and Menarini Stemline outside the submitted work. V. González-Calle reports personal fees from Johnson & Johnson and GSK and grants from Pfizer outside the submitted work. V. Cabañas reports grants and personal fees from Johnson & Johnson and personal fees from Bristol Myers Squibb, Amgen, BioGene, GSK, Menarini, Sanofi, and Pfizer outside the submitted work. B. Martin-Antonio reports a patent for EP4 007 777B1 issued. L. Pérez-Amill reports other support from Gyala Therapeutics S.L. outside the submitted work, as well as a patent for WO 2021/023,721 issued. P. Rodríguez-Otero reports personal fees from Bristol Myers Squibb, Johnson & Johnson Innovative Medicine, Regeneron, Pfizer, Sanofi, Roche, GSK, and AbbVie outside the submitted work. B. Paiva reports personal fees from Adaptive Biotech, Amgen, Becton Dickinson, Merck, Novartis, and Roche and grants and personal fees from Bristol Myers Squibb-Celgene, Janssen, Sanofi, and Takeda outside the submitted work. J. Martínez-López reports grants, personal fees, and nonfinancial support from Johnson & Johnson, Pfizer, Sanofi, and Bristol Myers Squibb and personal fees and nonfinancial support from GSK during the conduct of the study. M.-V. Mateos reports personal fees from Janssen, Bristol Myers Squibb, Amgen, GSK, Sanofi, Pfizer, Kite Pharma, AbbVie, AstraZeneca, Roche, Oncopeptides, and Stemline Therapeutics outside the submitted work. A. Urbano-Ispizua reports a patent for PCT/EP2020/071,831 issued. C. Fernández de Larrea reports grants and personal fees from Bristol Myers Squibb, Johnson & Johnson, Amgen, and GSK and personal fees from Sanofi, BeiGene, Pfizer, Oncopeptides, and Menarini outside the submitted work. M. Juan reports nonfinancial support and other support from Gyala Therapeutics S.L. outside the submitted work. No disclosures were reported by the other authors.

References

    1. Malard F, Neri P, Bahlis NJ, Terpos E, Moukalled N, Hungria VTM, et al. Multiple myeloma. Nat Rev Dis Primers 2024;10:45. - PubMed
    1. June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science 2018;359:1361–5. - PubMed
    1. June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med 2018;379:64–73. - PMC - PubMed
    1. Baker DJ, Arany Z, Baur JA, Epstein JA, June CH. CAR T therapy beyond cancer: the evolution of a living drug. Nature 2023;619:707–15. - PubMed
    1. Sheykhhasan M, Ahmadieh-Yazdi A, Vicidomini R, Poondla N, Tanzadehpanah H, Dirbaziyan A, et al. CAR T therapies in multiple myeloma: unleashing the future. Cancer Gene Ther 2024;31:667–86. - PMC - PubMed

Substances