A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy

Stein-Thoeringer CK, Saini NY, Zamir E, Blumenberg V, Schubert ML, Mor U, Fante MA, Schmidt S, Hayase E, Hayase T, Rohrbach R, Chang CC, McDaniel L, Flores I, Gaiser R, Edinger M, Wolff D, Heidenreich M, Strati P, Nair R, Chihara D, Fayad LE, Ahmed S, Iyer SP, Steiner RE, Jain P, Nastoupil LJ, Westin J, Arora R, Wang ML, Turner J, Menges M, Hidalgo-Vargas M, Reid K, Dreger P, Schmitt A, Müller-Tidow C, Locke FL, Davila ML, Champlin RE, Flowers CR, Shpall EJ, Poeck H, Neelapu SS, Schmitt M, Subklewe M, Jain MD, Jenq RR, Elinav E (2023)

Publication Type: Journal article

Publication year: 2023

Journal

Nature Medicine Nature Publishing Group

DOI: 10.1038/s41591-023-02234-6

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.

Involved external institutions

Universitätsklinikum Heidelberg DE Germany (DE) Weizmann Institute of Science IL Israel (IL) Universitätsklinikum Regensburg DE Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) University of Texas MD Anderson Cancer Center US United States (USA) (US) Bayerisches Zentrum für Krebsforschung (BZKF) DE Germany (DE) H. Lee Moffitt Cancer Center & Research Institute US United States (USA) (US) Klinikum der Universität München DE Germany (DE)

How to cite

APA:

Stein-Thoeringer, C.K., Saini, N.Y., Zamir, E., Blumenberg, V., Schubert, M.L., Mor, U.,... Elinav, E. (2023). A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy. Nature Medicine. https://doi.org/10.1038/s41591-023-02234-6

MLA:

Stein-Thoeringer, Christoph K., et al. "A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy." Nature Medicine (2023).

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