Journal Article

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

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

2023

Overview

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. Conserved microbiome features across clinical and geographical variations may enable microbiome-based predictions of outcomes in CD19-targeted CAR-T cell immunotherapy

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/67/1059 / 692/308/575 / Akkermansia / Algorithms / Antibiotics / Antigens / Antigens, CD19 / B-cell lymphoma / Biomedical and Life Sciences / Biomedicine / Biosynthesis / Cancer / Cancer immunotherapy / Cancer Research / CD19 antigen / Cell therapy / Chimeric antigen receptors / Digestive system / Effectiveness / Gastrointestinal Microbiome - genetics / Geographical variations / Gut microbiota / Humans / Immunotherapy / Immunotherapy, Adoptive - adverse effects / Infectious Diseases / Intestinal microflora / Lymphocytes / Lymphocytes T / Lymphoma / Lymphoma, B-Cell / Machine learning / Metabolic Diseases / Microbiomes / Microbiota / Molecular Medicine / Neurosciences / Patients / Peptidoglycans / Receptors, Chimeric Antigen / Risk / T-Lymphocytes