In a phase 1 trial, 20 patients with advanced melanoma received a first-line treatment of fecal microbiota transplant (FMT) from a healthy donor followed by anti-PD-1 therapy. Treatment was safe; adverse events were low-grade and mainly ICB-related. Overall response rate was 65%, with four complete responses. Patient microbiome diversity increased after FMT and trended towards donor composition, but this change was only sustained in anti-PD-1 responders, who also increased blood ICOS+CD8+ T cells and histidine levels. Mice recolonized with patient samples and treated with FMT and anti-PD-1 recapitulated clinical antitumor responses.
Contributed by Alex Najibi
ABSTRACT: Fecal microbiota transplantation (FMT) represents a potential strategy to overcome resistance to immune checkpoint inhibitors in patients with refractory melanoma; however, the role of FMT in first-line treatment settings has not been evaluated. We conducted a multicenter phase I trial combining healthy donor FMT with the PD-1 inhibitors nivolumab or pembrolizumab in 20 previously untreated patients with advanced melanoma. The primary end point was safety. No grade 3 adverse events were reported from FMT alone. Five patients (25%) experienced grade 3 immune-related adverse events from combination therapy. Key secondary end points were objective response rate, changes in gut microbiome composition and systemic immune and metabolomics analyses. The objective response rate was 65% (13 of 20), including four (20%) complete responses. Longitudinal microbiome profiling revealed that all patients engrafted strains from their respective donors; however, the acquired similarity between donor and patient microbiomes only increased over time in responders. Responders experienced an enrichment of immunogenic and a loss of deleterious bacteria following FMT. Avatar mouse models confirmed the role of healthy donor feces in increasing anti-PD-1 efficacy. Our results show that FMT from healthy donors is safe in the first-line setting and warrants further investigation in combination with immune checkpoint inhibitors. ClinicalTrials.gov identifier NCT03772899 .
Author Info: (1) Research Center of the Centre Hospitalier de l'Universit de Montral, Montral (CRCHUM), Montreal, Quebec, Canada. Hematology-Oncology Division, Department of Medicine, Centre
Author Info: (1) Research Center of the Centre Hospitalier de l'Universit de Montral, Montral (CRCHUM), Montreal, Quebec, Canada. Hematology-Oncology Division, Department of Medicine, Centre Hospitalier de l'Universit de Montral (CHUM), Montreal, Quebec, Canada. (2) Department of Oncology, Western University, London, Ontario, Canada. Lawson Health Research Institute, London, Ontario, Canada. (3) Lady Davis Institute of the Jewish General Hospital, Segal Cancer Centre, Montreal, Quebec, Canada. Departments of Oncology and Medicine, McGill University, Montreal, Quebec, Canada. (4) Research Center of the Centre Hospitalier de l'Universit de Montral, Montral (CRCHUM), Montreal, Quebec, Canada. Hematology-Oncology Division, Department of Medicine, Centre Hospitalier de l'Universit de Montral (CHUM), Montreal, Quebec, Canada. (5) Research Center of the Centre Hospitalier de l'Universit de Montral, Montral (CRCHUM), Montreal, Quebec, Canada. (6) Department of Microbiology & Immunology, Western University, London, Ontario, Canada. Canadian Centre for Human Microbiome and Probiotics Research, London, Ontario, Canada. (7) Research Center of the Centre Hospitalier de l'Universit de Montral, Montral (CRCHUM), Montreal, Quebec, Canada. Peter Brojde Lung Cancer Center, Jewish General Hospital, Montreal, Quebec, Canada. (8) Lawson Health Research Institute, London, Ontario, Canada. Department of Microbiology & Immunology, Western University, London, Ontario, Canada. Canadian Centre for Human Microbiome and Probiotics Research, London, Ontario, Canada. (9) Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, St Mary's Hospital Campus, Imperial College London, London, UK. Section of Bioinformatics, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK. (10) Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy. (11) Department of Oncology, Western University, London, Ontario, Canada. (12) Department of Oncology, Western University, London, Ontario, Canada. (13) Research Center of the Centre Hospitalier de l'Universit de Montral, Montral (CRCHUM), Montreal, Quebec, Canada. Hematology-Oncology Division, Department of Medicine, Centre Hospitalier de l'Universit de Montral (CHUM), Montreal, Quebec, Canada. (14) Lady Davis Institute of the Jewish General Hospital, Segal Cancer Centre, Montreal, Quebec, Canada. Departments of Oncology and Medicine, McGill University, Montreal, Quebec, Canada. (15) Research Center of the Centre Hospitalier de l'Universit de Montral, Montral (CRCHUM), Montreal, Quebec, Canada. (16) Department of Microbiology & Immunology, Western University, London, Ontario, Canada. (17) Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy. (18) Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy. (19) Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy. (20) Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada. (21) Department of Oncology, Western University, London, Ontario, Canada. (22) Research Center of the Centre Hospitalier de l'Universit de Montral, Montral (CRCHUM), Montreal, Quebec, Canada. (23) Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, National Phenome Centre, Imperial College London, London, UK. Section of Bioanalytical Chemistry, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK. (24) Rosalind and Morris Goodman Cancer Institute, McGill University, Montral, Quebec, Canada. (25) Rosalind and Morris Goodman Cancer Institute, McGill University, Montral, Quebec, Canada. (26) Gustave Roussy Cancer Campus, Villejuif, France. Cancer Medicine Department, Gustave Roussy, Villejuif, France. Institut National de la Sant Et et de la Recherche Mdicale (INSERM) U1015, ClinicObiome, Equipe Labellise-28 Ligue Nationale contre le Cancer, Villejuif, France. Universit Paris-Saclay, Ile-de-France, France. (27) Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, St Mary's Hospital Campus, Imperial College London, London, UK. (28) Department of Medicine, Division of Infectious Diseases, Western University, London, Ontario, Canada. Division of Infectious Diseases, St Joseph's Health Care, London, Ontario, Canada. (29) Research Center of the Centre Hospitalier de l'Universit de Montral, Montral (CRCHUM), Montreal, Quebec, Canada. (30) Rosalind and Morris Goodman Cancer Institute, McGill University, Montral, Quebec, Canada. Department of Biochemistry, McGill University, Montral, Quebec, Canada. (31) Research Center of the Centre Hospitalier de l'Universit de Montral, Montral (CRCHUM), Montreal, Quebec, Canada. Dpartement de Mdecine, Facult de Mdecine, Universit de Montral, Montral, Quebec, Canada. (32) Department of Computational, Cellular and Integrative Biology, University of Trento, Trento, Italy. (33) Lawson Health Research Institute, London, Ontario, Canada. Department of Microbiology & Immunology, Western University, London, Ontario, Canada. Department of Medicine, Division of Clinical Immunology and Allergy, Western University, London, Ontario, Canada. Department of Surgery, Division of General Surgery, Western University, London, Ontario, Canada. (34) Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, St Mary's Hospital Campus, Imperial College London, London, UK. Departments of Gastroenterology and Hepatology, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK. (35) Lawson Health Research Institute, London, Ontario, Canada. Department of Microbiology & Immunology, Western University, London, Ontario, Canada. Department of Medicine, Division of Infectious Diseases, Western University, London, Ontario, Canada. Division of Infectious Diseases, St Joseph's Health Care, London, Ontario, Canada. (36) Lawson Health Research Institute, London, Ontario, Canada. Department of Microbiology & Immunology, Western University, London, Ontario, Canada. Canadian Centre for Human Microbiome and Probiotics Research, London, Ontario, Canada. (37) Department of Oncology, Western University, London, Ontario, Canada. saman.malekivareki@lhsc.on.ca. Lawson Health Research Institute, London, Ontario, Canada. saman.malekivareki@lhsc.on.ca. Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada. saman.malekivareki@lhsc.on.ca. Department of Medical Biophysics, Western University, London, Ontario, Canada. saman.malekivareki@lhsc.on.ca. Ontario Institute of Cancer Research, Toronto, Ontario, Canada. saman.malekivareki@lhsc.on.ca.
