Journal article
A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy
Nature medicine, Vol.29(4), pp.906-916
01/Apr/2023
PMID: 36914893
Abstract
Increasing evidence suggests that the gut microbiome may modulate the efficacy of cancer immunotherapy. In a B cell lymphoma patient cohort from five centers in Germany and the United States (Germany, n = 66; United States, n = 106; total, n = 172), we demonstrate that wide-spectrum antibiotics treatment (‘high-risk antibiotics’) prior to CD19-targeted chimeric antigen receptor (CAR)-T cell therapy is associated with adverse outcomes, but this effect is likely to be confounded by an increased pretreatment tumor burden and systemic inflammation in patients pretreated with high-risk antibiotics. To resolve this confounding effect and gain insights into antibiotics-masked microbiome signals impacting CAR-T efficacy, we focused on the high-risk antibiotics non-exposed patient population. Indeed, in these patients, significant correlations were noted between pre-CAR-T infusion Bifidobacterium longum and microbiome-encoded peptidoglycan biosynthesis, and CAR-T treatment-associated 6-month survival or lymphoma progression. Furthermore, predictive pre-CAR-T treatment microbiome-based machine learning algorithms trained on the high-risk antibiotics non-exposed German cohort and validated by the respective US cohort robustly segregated long-term responders from non-responders. Bacteroides, Ruminococcus, Eubacterium and Akkermansia were most important in determining CAR-T responsiveness, with Akkermansia also being associated with pre-infusion peripheral T cell levels in these patients. Collectively, we identify conserved microbiome features across clinical and geographical variations, which may enable cross-cohort microbiome-based predictions of outcomes in CAR-T cell immunotherapy.
Details
- Title
- A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy
- Creators
- Christoph K. Stein-Thoeringer - University of TübingenNeeraj Y. Saini - MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Houston, TX 77030 USAEli Zamir - HeidelbergViktoria Blumenberg - LMU Klinikum, Med Klin 3, Munich, GermanyMaria-Luisa Schubert - University Hospital HeidelbergUria Mor - 972WIS_INST___121Matthias A. Fante - Univ Clin Regensburg, Dept Internal Med 3, Regensburg, GermanySabine Schmidt - German Cancer Research CenterEiko Hayase - The University of Texas MD Anderson Cancer CenterTomo Hayase - The University of Texas MD Anderson Cancer CenterRoman Rohrbach - German Cancer Research CenterChia-Chi Chang - The University of Texas MD Anderson Cancer CenterLauren McDaniel - The University of Texas MD Anderson Cancer CenterIvonne Flores - The University of Texas MD Anderson Cancer CenterRogier Gaiser - German Cancer Research CenterMatthias Edinger - German Canc Consortium DKTK, Munich, GermanyDaniel Wolff - German Canc Consortium DKTK, Munich, GermanyMartin Heidenreich - German Canc Consortium DKTK, Munich, GermanyPaolo Strati - MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USARanjit Nair - MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USADai Chihara - MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USALuis E. Fayad - MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USASairah Ahmed - MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USASwaminathan P. Iyer - MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USARaphael E. Steiner - MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USAPreetesh Jain - MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USALoretta J. Nastoupil - MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USAJason Westin - MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USAReetakshi Arora - The University of Texas MD Anderson Cancer CenterMichael L. Wang - MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USAJoel Turner - Moffitt Cancer CenterMeghan Menges - Moffitt Cancer CenterMelanie Hidalgo-Vargas - Moffitt Cancer CenterKayla Reid - Moffitt Cancer CenterPeter Dreger - University Hospital HeidelbergAnita Schmitt - University Hospital HeidelbergCarsten Mueller-Tidow - HeidelbergFrederick L. Locke - H Lee Moffitt Canc Ctr & Res Inst, Blood & Marrow Transplant & Cellular Immunotherap, Tampa, FL 33620 USAMarco L. Davila - H Lee Moffitt Canc Ctr & Res Inst, Blood & Marrow Transplant & Cellular Immunotherap, Tampa, FL 33620 USARichard E. Champlin - MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Houston, TX 77030 USAChristopher R. Flowers - MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USAElizabeth J. Shpall - The University of Texas MD Anderson Cancer CenterHendrik Poeck - Leibniz Institute for NeurobiologySattva S. Neelapu - MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USAMichael Schmitt - HeidelbergMarion Subklewe - LMU Klinikum, Med Klin 3, Munich, GermanyMichael D. Jain - H Lee Moffitt Canc Ctr & Res Inst, Blood & Marrow Transplant & Cellular Immunotherap, Tampa, FL 33620 USARobert R. Jenq - The University of Texas MD Anderson Cancer CenterEran Elinav - 972WIS_INST___121
- Resource Type
- Journal article
- Publication Details
- Nature medicine, Vol.29(4), pp.906-916; 01/Apr/2023
- Number of pages
- 33
- Publisher
- NATURE PORTFOLIO
- Language
- English
- DOI
- https://doi.org/10.1038/s41591-023-02234-6
- PMID
- 36914893
- Grant note
- We thank the members of the DKFZ Microbiome & Cancer Division and the Elinav laboratory, Weizmann Institute of Science for insightful discussions; and the participants, investigators, collaborators and study site personnel engaging in the trials. We also thank the REG allo-SCT/CAR team, especially H. Bremm, T. Schifferstein and Y. Schumann for their help in collecting and cryopreserving stool samples, and S. Gleich for data management. We are grateful for the partnership with the Mark Foundation (Endeavor Award 2021 to C.K.S.-T., E.E., R.R.J., M.D.J., M.L.D.), which funded key aspects of this study. C.K.S.-T. is supported by the German José Carreras Leukemia Foundation (01 R/2020), the German Research Foundation (DFG; STE 2964/5-1), the Baden-Württemberg Stiftung (MiCART19), the DFG Excellence Cluster EXC-2124 (Controlling Microbes to Fight Infections, CMFI) and the NCT Heidelberg Funds against Cancer. V.B. is supported by the Else-Kröner Fresenius-Stiftung and the German Cancer Consortium (DKTK) and the Bavarian Cancer for Cancer Research (BZKF). M.-L.S. is supported by the Olympia Morata Program of the University of Heidelberg (OM 09/2019). H.P. is supported by the DFG (Projektnummer 360372040 [SFB1335], 395357507 [SFB1371], 324392634 [TRR221]), German Cancer Aid (70114547), the Wilhelm Sander Foundation (2021.040.1), and by the EMBO Young Investigator Program. This study was supported by the generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Moon Shots Program, the Plaform for Innovative Microbiome and Translational Research (PRIME-TR) at the Department of Genomic Medicine at The University of Texas MD Anderson Cancer Center. This work was supported in part by a Cancer Center Support Grant (P30CA016672) from the National Cancer Institute and the Microbiome Core Facility at MD Anderson Cancer Center, and by a Cancer Center Support Grant (P30 CA076292) from the National Cancer Institute to Moffitt Cancer Center and the Moffitt Flow Cytometry Core Facility. R.R.J. is supported by R01HL124112 from the National Institutes of Health. E.E. is supported by the European Research Council, Israel Science Foundation, Israel Ministry of Science and Technology, Israel Ministry of Health, Helmholtz Foundation, Garvan Institute of Medical Research, European Crohn’s and Colitis Organization, Deutsch-Israelische Projektkooperation, IDSA Foundation and Wellcome Trust, and the Charlie Teo Foundation. E.E. is the incumbent of the Sir Marc and Lady Tania Feldmann Professorial Chair, a senior fellow of the Canadian Institute of Advanced Research (CIFAR) and an international scholar of the Bill & Melinda Gates Foundation and Howard Hughes Medical Institute (HHMI).
- Record Identifier
- 993434683203596
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