N Chaput1,2, P Lepage3, C Coutzac1,4, E Soularue1,4,5, K Le Roux3, C Monot3, L Boselli1, E Routier6, L Cassard1, M Collins4,5, T Vaysse4,5, L Marthey4,5, A Eggermont6,7, V Asvatourian8,9, E Lanoy8,9, C Mateus4, C Robert4,6, F Carbonnel4,5. 1. Laboratory of Immunomonitoring in Oncology, CNRS-UMS 3655 and INSERM-US23, Gustave Roussy Cancer Campus, Villejuif. 2. Faculty of Pharmacy, Chatenay-Malabry. 3. Micalis Institute, INRA, AgroParisTech, Paris. 4. Faculty of Medicine, University Paris-Saclay, Le Kremlin Bicêtre. 5. Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre. 6. Dermatology Unit, Department of Medicine, Gustave Roussy, Cancer Campus, Villejuif. 7. INSERM U1015, Gustave Roussy, Cancer Campus, Villejuif. 8. Biostatistics and Epidemiology Unit, Gustave Roussy Cancer Campus (GRCC), Villejuif. 9. University Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France.
Abstract
BACKGROUND: Ipilimumab, an immune checkpoint inhibitor targeting CTLA-4, prolongs survival in a subset of patients with metastatic melanoma (MM) but can induce immune-related adverse events, including enterocolitis. We hypothesized that baseline gut microbiota could predict ipilimumab anti-tumor response and/or intestinal toxicity. PATIENTS AND METHODS: Twenty-six patients with MM treated with ipilimumab were prospectively enrolled. Fecal microbiota composition was assessed using 16S rRNA gene sequencing at baseline and before each ipilimumab infusion. Patients were further clustered based on microbiota patterns. Peripheral blood lymphocytes immunophenotypes were studied in parallel. RESULTS: A distinct baseline gut microbiota composition was associated with both clinical response and colitis. Compared with patients whose baseline microbiota was driven by Bacteroides (cluster B, n = 10), patients whose baseline microbiota was enriched with Faecalibacterium genus and other Firmicutes (cluster A, n = 12) had longer progression-free survival (P = 0.0039) and overall survival (P = 0.051). Most of the baseline colitis-associated phylotypes were related to Firmicutes (e.g. relatives of Faecalibacterium prausnitzii and Gemmiger formicilis), whereas no colitis-related phylotypes were assigned to Bacteroidetes. A low proportion of peripheral blood regulatory T cells was associated with cluster A, long-term clinical benefit and colitis. Ipilimumab led to a higher inducible T-cell COStimulator induction on CD4+ T cells and to a higher increase in serum CD25 in patients who belonged to Faecalibacterium-driven cluster A. CONCLUSION: Baseline gut microbiota enriched with Faecalibacterium and other Firmicutes is associated with beneficial clinical response to ipilimumab and more frequent occurrence of ipilimumab-induced colitis.
BACKGROUND: Ipilimumab, an immune checkpoint inhibitor targeting CTLA-4, prolongs survival in a subset of patients with metastatic melanoma (MM) but can induce immune-related adverse events, including enterocolitis. We hypothesized that baseline gut microbiota could predict ipilimumab anti-tumor response and/or intestinal toxicity. PATIENTS AND METHODS: Twenty-six patients with MM treated with ipilimumab were prospectively enrolled. Fecal microbiota composition was assessed using 16S rRNA gene sequencing at baseline and before each ipilimumab infusion. Patients were further clustered based on microbiota patterns. Peripheral blood lymphocytes immunophenotypes were studied in parallel. RESULTS: A distinct baseline gut microbiota composition was associated with both clinical response and colitis. Compared with patients whose baseline microbiota was driven by Bacteroides (cluster B, n = 10), patients whose baseline microbiota was enriched with Faecalibacterium genus and other Firmicutes (cluster A, n = 12) had longer progression-free survival (P = 0.0039) and overall survival (P = 0.051). Most of the baseline colitis-associated phylotypes were related to Firmicutes (e.g. relatives of Faecalibacterium prausnitzii and Gemmiger formicilis), whereas no colitis-related phylotypes were assigned to Bacteroidetes. A low proportion of peripheral blood regulatory T cells was associated with cluster A, long-term clinical benefit and colitis. Ipilimumab led to a higher inducible T-cell COStimulator induction on CD4+ T cells and to a higher increase in serum CD25 in patients who belonged to Faecalibacterium-driven cluster A. CONCLUSION: Baseline gut microbiota enriched with Faecalibacterium and other Firmicutes is associated with beneficial clinical response to ipilimumab and more frequent occurrence of ipilimumab-induced colitis.
Authors: P Urwyler; I Earnshaw; M Bermudez; E Perucha; W Wu; S Ryan; L Mcdonald; S N Karagiannis; L S Taams; N Powell; A Cope; S Papa Journal: Clin Exp Immunol Date: 2020-02-21 Impact factor: 4.330
Authors: Md Abdul Wadud Khan; Gabriel Ologun; Reetakshi Arora; Jennifer L McQuade; Jennifer A Wargo Journal: Dig Dis Sci Date: 2020-03 Impact factor: 3.199