In patients with r/r-lymphoma, exposure to antibiotics, especially certain “‘high-risk”’ broad-spectrum antibiotics, prior to CD19-CAR-T therapy correlated with poorer patient survival. Patients pre-treated with these antibiotics had abnormal blood T cell numbers and phenotypes, but confounding effects of increased tumor burden and systemic inflammation. Unraveling these effects by focusing on patients not treated with high-risk antibiotics revealed their true impact on reduced gut microbial diversity, including predominance of new bacterial species and metabolic pathways. Bacterial composition also differed based on resident country or health, and species beneficial or harmful for CAR-T efficacy were found.
Contributed by Alex Najibi
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.
Author Info: (1) Division of Microbiome and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. Internal Medicine I, University Clinic Tuebingen, Tuebingen, Germany. (2) Departme
Author Info: (1) Division of Microbiome and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. Internal Medicine I, University Clinic Tuebingen, Tuebingen, Germany. (2) Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA. nsaini@mdanderson.org. Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX, USA. nsaini@mdanderson.org. (3) Division of Microbiome and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. (4) Medizinische Klinik III, LMU Klinikum, Munich, Germany. Laboratory for Translational Cancer Immunology, Gene Center of the LMU Munich, Munich, Germany. German Cancer Consortium (DKTK) and Bavarian Center for Cancer Research (BZKF), partner site Munich, Munich, Germany. (5) Department of Hematology, Oncology and Rheumatology, University Clinic Heidelberg, Heidelberg, Germany. (6) Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel. (7) Department of Internal Medicine III, University Clinic Regensburg, Regensburg, Germany. (8) Division of Microbiome and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. (9) Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX, USA. (10) Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX, USA. (11) Division of Microbiome and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. (12) Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX, USA. (13) Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX, USA. (14) Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX, USA. (15) Division of Microbiome and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. (16) German Cancer Consortium (DKTK) and Bavarian Center for Cancer Research (BZKF), partner site Munich, Munich, Germany. Department of Internal Medicine III, University Clinic Regensburg, Regensburg, Germany. Leibnitz Institut fr Immuntherapie (LIT), Regensburg, Germany. (17) German Cancer Consortium (DKTK) and Bavarian Center for Cancer Research (BZKF), partner site Munich, Munich, Germany. Department of Internal Medicine III, University Clinic Regensburg, Regensburg, Germany. Leibnitz Institut fr Immuntherapie (LIT), Regensburg, Germany. (18) German Cancer Consortium (DKTK) and Bavarian Center for Cancer Research (BZKF), partner site Munich, Munich, Germany. Leibnitz Institut fr Immuntherapie (LIT), Regensburg, Germany. (19) Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX, USA. (20) Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX, USA. (21) Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX, USA. (22) Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX, USA. (23) Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX, USA. (24) Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX, USA. (25) Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX, USA. (26) Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX, USA. (27) Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX, USA. (28) Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX, USA. (29) Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX, USA. (30) Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX, USA. (31) Department of Clinical Science, Moffitt Cancer Center, Tampa, FL, USA. (32) Department of Clinical Science, Moffitt Cancer Center, Tampa, FL, USA. (33) Department of Clinical Science, Moffitt Cancer Center, Tampa, FL, USA. (34) Department of Clinical Science, Moffitt Cancer Center, Tampa, FL, USA. (35) Department of Hematology, Oncology and Rheumatology, University Clinic Heidelberg, Heidelberg, Germany. (36) Department of Hematology, Oncology and Rheumatology, University Clinic Heidelberg, Heidelberg, Germany. (37) Department of Hematology, Oncology and Rheumatology, University Clinic Heidelberg, Heidelberg, Germany. (38) Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center and Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, FL, USA. (39) Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center and Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, FL, USA. (40) Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA. (41) Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX, USA. (42) Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA. (43) German Cancer Consortium (DKTK) and Bavarian Center for Cancer Research (BZKF), partner site Munich, Munich, Germany. Department of Internal Medicine III, University Clinic Regensburg, Regensburg, Germany. Leibnitz Institut fr Immuntherapie (LIT), Regensburg, Germany. (44) Department of Lymphoma and Myeloma, MD Anderson Cancer Center, Houston, TX, USA. (45) Department of Hematology, Oncology and Rheumatology, University Clinic Heidelberg, Heidelberg, Germany. (46) Medizinische Klinik III, LMU Klinikum, Munich, Germany. Laboratory for Translational Cancer Immunology, Gene Center of the LMU Munich, Munich, Germany. German Cancer Consortium (DKTK) and Bavarian Center for Cancer Research (BZKF), partner site Munich, Munich, Germany. (47) Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center and Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, FL, USA. michael.jain@moffitt.org. (48) Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA. rrjenq@mdanderson.org. Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX, USA. rrjenq@mdanderson.org. CPRIT Scholar in Cancer Research, University of Texas, Houston, USA. rrjenq@mdanderson.org. (49) Division of Microbiome and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. e.elinav@dkfz-heidelberg.de. Systems Immunology Department, Weizmann Institute of Science, Rehovot, Israel. e.elinav@dkfz-heidelberg.de.
