Antibiotic-induced loss of gut microbiome metabolic output correlates with clinical responses to CAR T-cell therapy
Abstract
Abstract 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.
Article Details
Authors (50)
Rishika Prasad
1Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Abdur Rehman
Lubna Rehman
1The University of Texas - MD Anderson Cancer Center, Lymphoma & Myeloma, Houston, United States
Faezeh Darbaniyan
1The University of Texas - MD Anderson Cancer Center, Lymphoma & Myeloma, Houston, United States
Viktoria Blumenberg
1Cellular Immunotherapy Program, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA
Maria-Luisa Schubert
Uria Mor
7Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel
Eli Zamir
8Division of Microbiome and Cancer, German Cancer Consortium, Heidelberg, Germany
Sabine Schmidt
Tomo Hayase
1The University of Texas MD Anderson Cancer Center, Houston, United States
Chia-Chi Chang
Department of Genomic Medicine and MDACC Epigenomics Therapy Initiative, The University of Texas MD Anderson Cancer Center
Lauren McDaniel
1Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Ivonne Flores
1Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Paolo Strati
Ranjit Nair
Dai Chihara
Luis E. Fayad
Sairah Ahmed
2Department of Lymphoma/Myeloma, MD Anderson Cancer Center, Houston, TX
Swaminathan P. Iyer
2Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
Michael Wang
Preetesh Jain
Loretta J. Nastoupil
Jason Westin
3Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX
Reetakshi Arora
2Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
Joel Turner
9Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL
Fareed Khawaja
1University of Texas, MD Anderson Cancer Center, Houston, United States
Ranran Wu
11Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX
Jennifer B. Dennison
11Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX
Meghan Menges
1H. Lee Moffitt Cancer Center, Hematology and Oncology, Tampa, United States
Melanie Hidalgo-Vargas
9Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL
Kayla Reid
1H. Lee Moffitt Cancer Center, Tampa, United States
Marco L. Davila
Peter Dreger
Felix Korell
Anita Schmitt
Mark R. Tanner
13Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
Richard E. Champlin
13Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
Christopher R. Flowers
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine
Elizabeth J. Shpall
Samir Hanash
11Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX
Sattva S. Neelapu
Michael Schmitt
Marion Subklewe
Ludwig Maximilian University Hospital, Munich, Germany
Johannes Francois-Fahrmann
11Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX
C. K. Stein-Thoeringer
14Department of Internal Medicine I, University Clinic Tüebingen, Tüebingen, Germany
Eran Elinav
Michael D. Jain
Eiko Hayase
1The University of Texas MD Anderson Cancer Center, Houston, United States
Robert R. Jenq
Department of Genomic Medicine and MDACC Epigenomics Therapy Initiative, The University of Texas MD Anderson Cancer Center
Neeraj Y. Saini
2Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX