In Nature medicine ; h5-index 170.0
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.
Stein-Thoeringer Christoph K, Saini Neeraj Y, Zamir Eli, Blumenberg Viktoria, Schubert Maria-Luisa, Mor Uria, Fante Matthias A, Schmidt Sabine, Hayase Eiko, Hayase Tomo, Rohrbach Roman, Chang Chia-Chi, McDaniel Lauren, Flores Ivonne, Gaiser Rogier, Edinger Matthias, Wolff Daniel, Heidenreich Martin, Strati Paolo, Nair Ranjit, Chihara Dai, Fayad Luis E, Ahmed Sairah, Iyer Swaminathan P, Steiner Raphael E, Jain Preetesh, Nastoupil Loretta J, Westin Jason, Arora Reetakshi, Wang Michael L, Turner Joel, Menges Meghan, Hidalgo-Vargas Melanie, Reid Kayla, Dreger Peter, Schmitt Anita, Müller-Tidow Carsten, Locke Frederick L, Davila Marco L, Champlin Richard E, Flowers Christopher R, Shpall Elizabeth J, Poeck Hendrik, Neelapu Sattva S, Schmitt Michael, Subklewe Marion, Jain Michael D, Jenq Robert R, Elinav Eran
2023-Mar-13
