Data from Microbiota Shape Metabolic and Immune Determinants of CAR-T Therapy and Correlate with Outcomes in Myeloma
<div>Abstract<p>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<sup>+</sup> 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, <i>Acidaminococcaceae</i>, <i>Monoglobaceae</i>, or <i>Akkermansiaceae</i>, 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.</p>Significance:<p>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.</p></div>
Authors
- Iñaki Ortiz de Landazuri (ORCID: https://orcid.org/0000-0003-0953-0510)
- Núria Amigó (ORCID: https://orcid.org/0000-0002-0116-9145)
- Juan Luis Reguera (ORCID: https://orcid.org/0009-0009-6408-1747)
- Elisa Rubio-García (ORCID: https://orcid.org/0000-0002-2556-8837)
- Álvaro Urbano-Ispizúa (ORCID: https://orcid.org/0000-0002-7529-9399)
- Julio Delgado (ORCID: https://orcid.org/0000-0002-5157-4376)
- Andrea Vergara (ORCID: https://orcid.org/0000-0002-5046-4490)
- Roberto Martínez-Soler (ORCID: https://orcid.org/0000-0003-1557-4456)
- Mariona Pascal (ORCID: https://orcid.org/0000-0003-0549-9720)
- Luis Gerardo Rodríguez‐Lobato (ORCID: https://orcid.org/0000-0001-5694-0921)
- María‐Victoria Mateos (ORCID: https://orcid.org/0000-0003-2390-1218)
- Marta Español‐Rego (ORCID: https://orcid.org/0000-0001-5497-2276)
- Nela Klein-González (ORCID: https://orcid.org/0000-0002-4593-6457)
- Joaquín Martínez‐López (ORCID: https://orcid.org/0000-0001-7908-0063)
- Neus Martínez-Micaelo (ORCID: https://orcid.org/0000-0001-6101-2847)
- Carlos Fernández de Larrea (ORCID: https://orcid.org/0000-0003-4930-9255)
- Maria Val-Casals (ORCID: https://orcid.org/0000-0003-2481-3295)
- Mireia Uribe‐Herranz (ORCID: https://orcid.org/0000-0002-2618-1116)
- Verónica González‐Calle (ORCID: https://orcid.org/0000-0002-5493-6707)
- Valentín Ortiz‐Maldonado (ORCID: https://orcid.org/0000-0003-4699-6862)
- Aina Oliver‐Caldés (ORCID: https://orcid.org/0000-0002-7921-5420)
- Bruno Paiva (ORCID: https://orcid.org/0000-0003-1977-3815)
- Valentín Cabañas (ORCID: https://orcid.org/0000-0002-6248-2549)
- Europa Azucena González‐Navarro (ORCID: https://orcid.org/0000-0003-3310-5557)
- Manel Juan (ORCID: https://orcid.org/0000-0002-3064-1648)
- Beatriz Martín-Antonio (ORCID: https://orcid.org/0000-0003-0612-2693)
- Lorena Pérez-Amill (ORCID: https://orcid.org/0000-0003-0674-4660)
- Daniel Benítez‐Ribas (ORCID: https://orcid.org/0000-0002-2346-5324)
- Paula Rodríguez‐Otero (ORCID: https://orcid.org/0000-0001-5236-7785)
- Erik Z. Mihelic (ORCID: https://orcid.org/0009-0006-2168-9814)
- Valeria Brunello (ORCID: https://orcid.org/0009-0001-4754-0317)
Publication Details
- Published
- 2025-09-03
- DOI
- https://doi.org/10.1158/2643-3230.c.8014450
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 0.00