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Antibiotic-induced loss of gut microbiome metabolic output correlates with clinical responses to CAR T-cell therapy

Antibiotic (ABX)-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-cell (CAR-T) therapies. In this study, we observed that prior exposure to broad-...

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Main Authors: Prasad, Rishika (Author) , Rehman, Abdur (Author) , Rehman, Lubna (Author) , Darbaniyan, Faezeh (Author) , Blumenberg, Viktoria (Author) , Schubert, Maria-Luisa (Author) , Mor, Uria (Author) , Zamir, Eli (Author) , Schmidt, Sabine (Author) , Hayase, Tomo (Author) , Chang, Chia-Chi (Author) , McDaniel, Lauren (Author) , Flores, Ivonne (Author) , Strati, Paolo (Author) , Nair, Ranjit (Author) , Chihara, Dai (Author) , Fayad, Luis E. (Author) , Ahmed, Sairah (Author) , Iyer, Swaminathan P. (Author) , Wang, Michael (Author) , Jain, Preetesh (Author) , Nastoupil, Loretta J. (Author) , Westin, Jason (Author) , Arora, Reetakshi (Author) , Turner, Joel (Author) , Khawaja, Fareed (Author) , Wu, Ranran (Author) , Dennison, Jennifer B. (Author) , Menges, Meghan (Author) , Hidalgo-Vargas, Melanie (Author) , Reid, Kayla (Author) , Davila, Marco L. (Author) , Dreger, Peter (Author) , Korell, Felix (Author) , Schmitt, Anita (Author) , Tanner, Mark R. (Author) , Champlin, Richard E. (Author) , Flowers, Christopher R. (Author) , Shpall, Elizabeth J. (Author) , Hanash, Samir (Author) , Neelapu, Sattva S. (Author) , Schmitt, Michael (Author) , Subklewe, Marion (Author) , Francois-Fahrmann, Johannes (Author) , Stein-Thoeringer, C. K. (Author) , Elinav, Eran (Author) , Jain, Michael D. (Author) , Hayase, Eiko (Author) , Jenq, Robert R. (Author) , Saini, Neeraj Y. (Author)
Format: Article (Journal)
Language:English
Published: February 20, 2025
In: Blood
Year: 2025, Volume: 145, Issue: 8, Pages: 823-839
ISSN:1528-0020
DOI:10.1182/blood.2024025366
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1182/blood.2024025366
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Author Notes:Rishika Prasad, Abdur Rehman, Lubna Rehman, Faezeh Darbaniyan, Viktoria Blumenberg, Maria-Luisa Schubert, Uria Mor, Eli Zamir, Sabine Schmidt, Tomo Hayase, Chia-Chi Chang, Lauren McDaniel, Ivonne Flores, Paolo Strati, Ranjit Nair, Dai Chihara, Luis E. Fayad, Sairah Ahmed, Swaminathan P. Iyer, Michael Wang, Preetesh Jain, Loretta J. Nastoupil, Jason Westin, Reetakshi Arora, Joel Turner, Fareed Khawaja, Ranran Wu, Jennifer B. Dennison, Meghan Menges, Melanie Hidalgo-Vargas, Kayla Reid, Marco L. Davila, Peter Dreger, Felix Korell, Anita Schmitt, Mark R. Tanner, Richard E. Champlin, Christopher R. Flowers, Elizabeth J. Shpall, Samir Hanash, Sattva S. Neelapu, Michael Schmitt, Marion Subklewe, Johannes Francois-Fahrmann, C. K. Stein-Thoeringer, Eran Elinav, Michael D. Jain, Eiko Hayase, Robert R. Jenq, and Neeraj Y. Saini
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Summary:Antibiotic (ABX)-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-cell (CAR-T) therapies. In this study, we observed that prior exposure to broad-spectrum ABXs with extended anaerobic coverage such as piperacillin-tazobactam and meropenem was associated with worse anti-CD19 CAR-T therapy survival outcomes in patients with large B-cell lymphoma (N = 422) than other ABX classes. In a discovery subset of these patients (n = 67), we found that the use of these ABXs 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, in which 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-Ts, 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 efficacy. This highlights the potential for modulating the microbiome to augment CAR-T immunotherapy. This trial was registered at www.clinicaltrials.gov as #NCT06218602.
Item Description:Online verfügbar 28 October 2024, Version des Artikels 20 February 2025
Gesehen am 29.07.2025
Physical Description:Online Resource
ISSN:1528-0020
DOI:10.1182/blood.2024025366

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