A study published in the journal Science by a research team from Gustave Roussy, INSERM, INRA, AP-HP, IHU Médiaterranée Infections* and Paris-Sud University shows that prescribed antibiotics impair the efficacy of immunotherapy in cancer patients. It is important to consider that more than 20% of patients living with cancer receive antibiotics. The authors explored patients’ gut microbiota composition by metagenomic analysis and demonstrated that the bacterium Akkermansia muciniphila was associated with a better clinical response to anti-PD-1 antibody immunotherapy. Moreover, oral administration of this bacterium to mice with an unfavorable microbiota restored the anti-tumor activity of the immunotherapy.
This paper will be published online by the journal Science on Thursday, 2 November 2017.
Immunotherapy represents a real revolution in cancer therapies and has been shown to be superior to standard chemotherapy in advanced melanoma, lung, renal and bladder cancer. Although a large proportion of patients still do not benefit from this treatment, “Our research partially explains why some patients do not respond. Taking antibiotics has a deleterious impact on survival in patients receiving immunotherapy. Furthermore, the composition of the intestinal microbiota is a new predictive factor for success,” summarized Dr. Bertrand Routy, hematologist and member of the team of Professor Laurence Zitvogel, director of the “Immunology of tumors and immunotherapy” laboratory (Inserm/Paris-Sud University/Gustave Roussy).
In a cohort of 249 patients treated with anti-PD-1/PD-L1 based immunotherapy for advanced lung, kidney or bladder cancer, 28% received antibiotics for minor infections (dental, urinary or lung infections) but their general health status was not different from patients not receiving antibiotics.
Favorable microbiota determined by metagenomics
The precise composition of the gut microbiota was established by metagenomics both before and during immunotherapy in 153 patients with advanced lung or kidney cancer. The identification of all the bacterial genes present in the gut microbiota was performed by INRA (MetaGenoPolis, Dr. Emmanuelle Le Chatelier). A favorable microbiota composition, rich in Akkermansia muciniphila, was found in patients with the best clinical response to immunotherapy and in those whose disease had not progressed for at least 3 months.
Improving unfavorable microbiota
To demonstrate a direct cause and effect relationship between the composition of gut microbiota and the efficacy of immunotherapy, favorable microbiota (taken from patients who had a good response to PD-1 immunotherapy) and unfavorable microbiota (from patients with therapeutic failure) were transferred to mice deprived of gut microbiota. The mice receiving the favorable microbiota did better when treated with immunotherapy than those who received the unfavorable microbiota. In the latter group, oral administration of Akkermansia muciniphila resulted in the restoration of the efficacy of anti-PD-1 immunotherapy. Changing the microbiota in the mouse re-established the effectiveness of immunotherapy by activating certain immune cells.
Results simultaneously reported in the same edition of the journal by an american team (Dr. Jennifer Wargo, MD Anderson, Texas) support these findings showing that the composition of microbiota in melanoma patients predicts the response to anti-PD-1 immunotherapy.
This research is being carried out within the framework of the Torino-Lumière project (a 9 M€ “investissement d’avenir” [investment for the future] program). The objective of this unique study is to develop microbiome-based biomarkers that predict the response to immunotherapy in patients with lung cancer. This prospective multicenter study initiated in 2016 aims at determining unfavorable bacterial signatures to compensate patients with a combination of bacteria endowed with immunotherapeutic properties.
Immunotherapy has changed the way we treat various cancers. These novel immunotherapies include monoclonal antibodies (anti-CTLA4 or anti-PD1), transferring activated T-lymphocytes and bispecific agents, all boosting patient’s immune system. They not only reduce tumor size but also, and for the first time, significantly increase patient overall survival, eventually curing metastatic or locally advanced cancers in melanoma.
About gut microbiota
Gut microbiota (previously known as intestinal flora) represents a complex ecosystem consisting of 100,000 billion bacteria, viruses, archaea, parasites and yeasts. They colonize the bowel from birth and participate in the maturation of immune defense mechanisms. Individuals have their own specific microbiota. Its composition is a product of genetic, nutritional and environmental factors.
* Gustave Roussy = Leading comprehensive cancer center in Europe
INSERM = National Institute for Health and Medical Research
INRA = National Institute for Agronomic Research
AP-HP = Paris Public Hospitals
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Gut microbiome influences efficacy of PD-1 based-immunotherapy against epithelial tumors
Science, publication avancée en ligne du 2 novembre 2017
Bertrand Routy1,2,3, Emmanuelle Le Chatelier4, Lisa Derosa1,2,3, Connie P. M. Duong1,2,5, Maryam Tidjani Alou1,2,3, Romain Daillère1,2,3, Aurélie Fluckiger1,2,5, Meriem Messaoudene1,2, Conrad Rauber1,2,3, Maria P. Roberti1,2,5, Marine Fidelle1,3,5, Caroline Flament1,2,5, Vichnou Poirier-Colame1,2,5, Paule Opolon6, Christophe Klein7, Kristina Iribarren8,9,10,11,12, Laura Mondragón8,9,10,11,12, Nicolas Jacquelot1,2,3, Bo Qu1,2,3, Gladys Ferrere1,2,3, Céline Clémenson1,13, Laura Mezquita1,14, Jordi Remon Masip1,14, Charles Naltet15, Solenn Brosseau15, Coureche Kaderbhai16, Corentin Richard16, Hira Rizvi17, Florence Levenez4, Nathalie Galleron4, Benoit Quinquis4, Nicolas Pons4, Bernhard Ryffel18, Véronique Minard-Colin1,19, Patrick Gonin1,20, Jean-Charles Soria1,14, Eric Deutsch1,13, Yohann Loriot1,3,14, François Ghiringhelli16, Gérard Zalcman15, François Goldwasser9,21,22, Bernard Escudier1,14,23, Matthew D. Hellmann24,25, Alexander Eggermont1,2,14, Didier Raoult26, Laurence Albiges1,3,14, Guido Kroemer8-12,27,28*, and Laurence Zitvogel1,2,3,5*.
1Gustave Roussy Cancer Campus (GRCC), Villejuif, France.
2Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Villejuif, France. Equipe Labellisée—Ligue Nationale contre le Cancer, Villejuif, France.
3Univ. Paris-Sud, Université Paris-Saclay, Gustave Roussy, Villejuif, France.
4MGP MetaGénoPolis, INRA, Université Paris-Saclay, Jouy-en-Josas, France.
5Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France.
6Gustave Roussy, Laboratoire de Pathologie Expérimentale, 94800 Villejuif, France.
7Centre de Recherche des Cordeliers, INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMRS 1138, Université Pierre et Marie Curie Université Paris 06, Sorbonne Universités, Paris, France.
8Metabolomics and Cell Biology Platforms, GRCC, Villejuif, France.
9Paris Descartes University, Sorbonne Paris Cité, Paris, France.
10Equipe 11 Labellisée—Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers,Paris, France.
11Institut National de la Santé et de la Recherche Médicale, U1138, Paris, France.
12Pierre et Marie Curie University, Paris, France.
13Department of Radiation Oncology, Gustave Roussy, Université Paris-Saclay, F-94805 Villejuif, France; INSERM U1030, Molecular Radiotherapy, Gustave Roussy, Université Paris-Saclay.
14Department of Medical Oncology, Gustave Roussy, Villejuif, France.
15Thoracic Oncology Department-CIC1425/CLIP2 Paris-Nord, Hospital Bichat-Claude Bernard, AP-HP, University Paris-Diderot.
16Department of medical oncology, Center GF Leclerc, Dijon, France.
17Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
18Molecular Immunology and Embryology, UMR 7355, CNRS, University of Orleans, Orléans, France.
19Department of Pediatric Oncology, GRCC, Villejuif, France.
20Preclinical Research Platform, GRCC, Villejuif, France.
21Department of Medical Oncology, Cochin Hospital, Assistance Publique—Hôpitaux de Paris, Paris, France.
22Immunomodulatory Therapies Multidisciplinary Study group (CERTIM), Paris, France
23Institut National de la Santé Et de la Recherche Medicale (INSERM) U981, GRCC, Villejuif, France.
24Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
25Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
26URMITE, Aix Marseille Université, UM63, CNRS 7278, IRD 198, INSERM 1095, IHU – Méditerranée Infection, 19-21 Boulevard Jean Moulin, 13005 Marseille
27Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique—Hôpitaux de Paris, Paris, France.
28Department of Women’s and Children’s Health, Karolinska University Hospital, 17176 Stockholm, Sweden.