Journal Article

DKFZ-2024-02165

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Antibiotic-induced loss of gut microbiome metabolic output correlates with clinical responses to CAR T-cell therapy.

Prasad, R. ; Rehman, A. ; Rehman, L. ; Darbaniyan, F. ; Blumenberg, V.DKFZ* ; Schubert, M.-L. ; Mor, U. ; Zamir, E.DKFZ* ; Schmidt, S.DKFZ* ; Hayase, T. ; Chia-Chi, C. ; McDaniel, L. K. ; Flores, I. ; Strati, P. ; Nair, R. ; Chihara, D. ; Fayad, L. E. ; Ahmed, S. ; Iyer, S. P. ; Wang, M. L. ; Jain, P. ; Nastoupil, L. J. ; Westin, J. R. ; Arora, R. ; Turner, J. G. ; Khawaja, F. ; Wu, R. ; Dennison, J. B. ; Menges, M. ; Hidalgo-Vargas, M. ; Reid, K. M. ; Davila, M. L. ; Dreger, P. ; Korell, F. ; Schmitt, A. ; Tanner, M. R. ; Champlin, R. E. ; Flowers, C. R. ; Shpall, E. J. ; Hanash, S. ; Neelapu, S. S. ; Schmitt, M. ; Subklewe, M.DKFZ* ; Fahrmann, J. ; Stein-Thoeringer, C. ; Elinav, E.DKFZ* ; Jain, M. D. ; Hayase, E. ; Jenq, R. R. ; Saini, N. Y.

2025
American Society of Hematology Washington, DC

This record in other databases:  

Please use a persistent id in citations: doi:10.1182/blood.2024025366

Abstract: Antibiotic-induced microbiome dysbiosis is widespread in oncology, adversely affecting outcomes and side effects of various cancer treatments, including immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cell therapies. In this study, we observed that prior exposure to broad-spectrum ABX with extended anaerobic coverage like piperacillin-tazobactam and meropenem was associated with worsened anti-CD19 CAR-T therapy survival outcomes in large B-cell lymphoma patients (n=422), compared to other ABX classes. In a discovery subset of these patients (n=67), we found that the use of these ABX was in turn associated with substantial dysbiosis of gut microbiome function, resulting in significant alterations of the gut and blood metabolome, including microbial effectors such as short-chain fatty acids (SCFAs) and other anionic metabolites, findings that were largely reproduced in an external validation cohort (n=58). Broader evaluation of circulating microbial metabolites revealed reductions in indole and cresol derivatives, as well as trimethylamine N-oxide, in patients who received ABX treatment (discovery n=40, validation n=28). These findings were recapitulated in an immune-competent CAR-T mouse model, where meropenem-induced dysbiosis led to a systemic dysmetabolome and decreased murine anti-CD19 CAR-T efficacy. Furthermore, we demonstrate that SCFAs can enhance the metabolic fitness of CAR-T cells, leading to improved tumor killing capacity. Together, these results suggest that broad-spectrum ABX deplete metabolically active commensals whose metabolites are essential for enhancing CAR-T efficacy, shedding light on the intricate relationship between ABX exposure, microbiome function and their impact on CAR-T cell efficacy. This highlights the potential for modulating the microbiome to augment CAR-T immunotherapy.

Note: 2025 Feb 20;145(8):823-839

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Contributing Institute(s):

1. Mikrobiom und Krebs (D480)
2. DKTK Koordinierungsstelle München (MU01)
3. DKTK HD zentral (HD01)

Research Program(s):

1. 314 - Immunologie und Krebs (POF4-314) (POF4-314)

Appears in the scientific report 2024

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 20 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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