TY  - JOUR
AU  - Prasad, Rishika
AU  - Rehman, Abdur
AU  - Rehman, Lubna
AU  - Darbaniyan, Faezeh
AU  - Blumenberg, Viktoria
AU  - Schubert, Maria-Luisa
AU  - Mor, Uria
AU  - Zamir, Eli
AU  - Schmidt, Sabine
AU  - Hayase, Tomo
AU  - Chia-Chi, Chang
AU  - McDaniel, Lauren Kelley
AU  - Flores, Ivonne
AU  - Strati, Paolo
AU  - Nair, Ranjit
AU  - Chihara, Dai
AU  - Fayad, Luis E
AU  - Ahmed, Sairah
AU  - Iyer, Swaminathan P
AU  - Wang, Michael L
AU  - Jain, Preetesh
AU  - Nastoupil, Loretta J
AU  - Westin, Jason R
AU  - Arora, Reetakshi
AU  - Turner, Joel Gordon
AU  - Khawaja, Fareed
AU  - Wu, Ranran
AU  - Dennison, Jennifer B
AU  - Menges, Meghan
AU  - Hidalgo-Vargas, Melanie
AU  - Reid, Kayla M
AU  - Davila, Marco L
AU  - Dreger, Peter
AU  - Korell, Felix
AU  - Schmitt, Anita
AU  - Tanner, Mark R
AU  - Champlin, Richard E
AU  - Flowers, Christopher R
AU  - Shpall, Elizabeth J
AU  - Hanash, Samir
AU  - Neelapu, Sattva S
AU  - Schmitt, Michael
AU  - Subklewe, Marion
AU  - Fahrmann, Johannes
AU  - Stein-Thoeringer, Christoph
AU  - Elinav, Eran
AU  - Jain, Michael D
AU  - Hayase, Eiko
AU  - Jenq, Robert R
AU  - Saini, Neeraj Y
TI  - Antibiotic-induced loss of gut microbiome metabolic output correlates with clinical responses to CAR T-cell therapy.
JO  - Blood
VL  - 145
IS  - 8
SN  - 0006-4971
CY  - Washington, DC
PB  - American Society of Hematology
M1  - DKFZ-2024-02165
SP  - 823-839
PY  - 2025
N1  - 2025 Feb 20;145(8):823-839
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:39441941
DO  - DOI:10.1182/blood.2024025366
UR  - https://inrepo02.dkfz.de/record/294332
ER  -