It is now demonstrated that gut microbiota composition has a determining influence not only on inflammatory bowel diseases but also more broadly on the immunological status of healthy individuals as well as in patients with cancer. We explored the potential role of baseline gut microbiota in anti-tumor response and in intestinal toxicity of patients with metastatic melanoma treated with anti-CTLA4 mAb ipilimumab. Moreover we explored how the composition of gut microbiota could influence not only local gut-immunity but also distant sites such as anti-tumor immunity.
Fecal microbiota compositions were prospectively assessed at baseline and before each ipilimumab infusion, using 16S rRNA gene sequencing. Patients were further clustered based on microbiota patterns. Peripheral blood lymphocytes immunophenotypes were studied in parallel.
A distinct baseline gut microbiota composition was associated with both clinical response and colitis. As compared to patients whose baseline microbiota was driven by Bacteroides (Cluster B), patients whose baseline microbiota was enriched with Firmicutes (Cluster A) had longer progression-free survival and overall survival. Most of the baseline colitis-associated phylotypes were related to Firmicutes, whereas no-colitis related phylotypes were assigned to Bacteroides. 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 Cluster A.
Baseline gut microbiota enriched with Firmicutes is associated with beneficial clinical response to ipilimumab and more frequent occurrence of ipilimumab-induced colitis.
Clinical trial identification
GOLD study: SC12-018; ID-RCB-2012-A01496-37
Legal entity responsible for the study
Coordination: Franck Carbonnel (AP-HP)
This study was funded by academic groups only: 1- Gustave Roussy Cancer Campus 2- Fondation Gustave Roussy, 3- Direction Générale de l’Offre de Soins (DGOS; GOLD TRANSLA 12-174), 4- Institut National du Cancer (INCa; GOLD 2012-062 N° Cancéropôle: 2012-1-RT-14-IGR-01) 5- SIRIC SOCRATE (INCa DGOS INSERM 6043) 6- MMO program: ANR-10IBHU-0001.
N. Chaput: Grants from Cytune Pharma. E. Soularue: Medical Board for Novartis. F. Carbonnel: Advisory Board for Vifor, enterome, MSD (oncology), Ferring Lecture fees from Abbvie, Janssen, Mayoly Spindler, Hospira, Pfizer, Takeda Research Grants: Alpha Wassermann, Mayoly Spindler. C. Robert: Occasional consultant for Amgen, MSD, Merck, Novartis, Roche, Bristol-Myers Squibb. All other authors have declared no conflicts of interest.