The vital role of the intestinal flora in successful immunotherapy has just been revealed in a study published in the journal Science. Intestinal bacteria have been identified that can improve the therapeutic response to this drug and reduce a side-effect, “inflammatory colitis,” regularly encountered with this treatment.
This research implies that the efficacy of immunotherapy in oncology might in future be dictated by the composition of the patient’s intestinal flora. The researchers hope to develop a test for predicting the response to these treatments by analysing the intestinal flora. They also hope to offer those patients who need it the opportunity to reconstitute a flora which will restore the anti-tumour effect of the immunotherapy.
This research was conducted jointly by French researchers from Gustave Roussy, Inserm, Institut Pasteur Lille and Institut Pasteur Paris, the AP-HP (Paris Public Hospitals) and Paris-Sud University, in collaboration with a team from the French National Institute for Agricultural Research (INRA), and was mainly funded by ARC Foundation for Cancer Research.
“Certain bacteria naturally present in the intestinal flora are becoming the pillars of success for an immunotherapy used in clinical oncology,” comments Prof. Laurence Zitvogel, Director of the Tumour Immunology and Immunotherapy Laboratory (Inserm / Gustave Roussy / Paris-Sud University), and last author of the publication.
The role of two types of bacteria from the intestinal flora in the alleviation of these side-effects and in increasing the efficacy of an immunotherapy based on a monoclonal antibody against CTLA4 (ipilimumab) has just been demonstrated by Prof. Laurence Zitvogel’s team, with assistance from teams led by Dr Mathias Chamaillard, Institut Pasteur Lille, Dr Ivo Gomperts Boneca, Institut Pasteur Paris, and Dr Patricia Lepage, INRA.
The researchers showed that when the intestinal flora lacked the two bacterial types identified, either in germ-free mice or after treatment with broad-spectrum antibiotics, the drug was no longer effective against the tumour. Colonisation of the intestinal flora by one or other of these bacterial types is necessary and sufficient to restore the effect of the monoclonal antibody and improve the symptomatology of inflammatory colitis in these mice.
The relevance of these findings was also successfully tested in humans. The teams led by Prof. Caroline Robert, Head of the Dermatology Department in Gustave Roussy, and by Prof. Franck Carbonnel, Head of the Gastroenterology Department at Bicêtre Hospital, AP-HP, began a clinical trial in order to demonstrate the relevance of these findings in patients with melanoma.
Analysis of the intestinal flora of patients with metastatic melanoma following treatment with ipilimumab thus showed the importance of these immunogenic bacteria in sensitivity to the treatment and in tumour reduction. These results suggest that it is of interest to consider immunogenic bacteria as an adjuvant treatment for cancer.
“Concurrently with our work, an American team came to the same conclusions regarding the role of other bacteria in the efficacy of the anti-PD1 antibody nivolumab,” adds Prof. Laurence Zitvogel, who points out that this work shows that the microbiota dictates the therapeutic response, opening up interesting possibilities for treatment. We could thus offer patients with a relatively unfavourable intestinal flora a compensatory bacterial composition, whether by prebiotic treatment, by immunogenic bacteria from the intestinal flora, or by faecal transplant. However, there is a current lack of regulatory certainty in France regarding the transformation of intestinal flora into drugs that might become agents for adjuvant therapy in oncology with the help of legislators and regulatory agencies.
// About immunotherapy
Immunotherapies have enabled a revolution in cancer treatment. Not only do they make it possible to reduce the size of tumours, they also, for the first time, make it possible to prolong the survival of patients, or even cure them of metastatic or locally advanced cancer. These new immunotherapies, using monoclonal antibodies (anti-CTA4 or anti-PD1), make it possible to awaken the patient’s immune system. However, 20% of patients undergoing anti-CTLA4 treatment experience auto-immune side-effects such as “inflammatory colitis.”
// About the intestinal flora
The intestinal flora, or intestinal microbiota, is composed of 100,000 billion bacteria. These colonise the intestine from birth, and are involved in the maturation of the immune defences. Every individual has his/her own unique microbiota. The composition of this flora is dictated by genetic, nutritional and environmental factors. Certain bacteria can promote the occurrence of diseases; conversely, others have a protective effect.
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Article publié dans la revue ScienceAnticancer immunotherapy by CTLA4 blockade relies on the gut microbiotaMarie Vétizou1,2,3, Jonathan M. Pitt1,2,3, Romain Daillère1,2,3, Patricia Lepage5, Nadine Waldschmitt13, Caroline Flament1,2,4, Sylvie Rusakiewicz1,2,4, Bertrand Routy1,2,3, Maria P. Roberti1,2,4, Connie PM. Duong1,2,4, Vichnou Poirier-Colame1,2, Antoine Roux1,2,19, Sonia Becharef1,2,4, Silvia Formenti6, Encouse Golden6, Sascha Cording7, Gerard Eberl7, Andreas Schlitzer8, Florent Ginhoux8, Sridhar Mani12, Takahiro Yamazaki1,2, Nicolas Jacquelot1,2,3, David P. Enot1,10, Marion Bérard23, Jérôme Nigou14,15, Paule Opolon1, Alexander Eggermont1,2,16, Paul-Louis Woerther17, Elisabeth Chachaty17, Nathalie Chaput1,26, Caroline Robert1,16,24, Christina Matteus1,16, Guido Kroemer9,10,11,18,19, Didier Raoult20, Ivo Gomperts Boneca21,22†, Franck Carbonnel3,25†, Mathias Chamaillard13† , and Laurence Zitvogel1,2,3, 4*1 Institut de Cancérologie Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France.2 Institut National de la Santé Et de la Recherche Medicale (INSERM) U1015, GRCC, Villejuif, France.3 University of Paris Sud XI, Kremlin Bicêtre, France.4 Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France. 5 Institut National de la Recherche Agronomique (INRA), Micalis-UMR1319, 78360 Jouy-en-Josas, France.6 Department of Radiation Oncology, New York University, New York, NY, USA.7 Microenvironment & Immunity Unit, Institut Pasteur, Paris, France.8 Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore;9 INSERM U848, Villejuif, France.10 Metabolomics Platform, GRCC, Villejuif, France.11 Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France.12 Departments of Genetics and Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.13 Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 – UMR 8204 – CIIL - Centre d'Infection et d'Immunité de Lille, F-59000 Lille, France.14 Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale (IPBS), Toulouse, France.15 Université de Toulouse, Université Paul Sabatier, IPBS, F-31077 Toulouse, France.16 Department of Medical Oncology, IGR, Villejuif, France.17 Service de microbiologie, GRCC, Villejuif, France.18 Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.19 Université Paris Descartes, Sorbonne Paris Cité, Paris, France.20 Unité des Rickettsies, Faculté de Médecine, Université de la Méditerranée, Marseille, France.21 Institut Pasteur, Unit Biology and Genetics of the bacterial Cell Wall, Paris, France.22 INSERM, Equipe Avenir, Paris, France.23 Animalerie Centrale, Institut Pasteur, Paris, France.24 Institut National de la Santé Et de la Recherche Medicale (INSERM) U981, GRCC, Villejuif, France.25 Gastroenterology department Hôpital Bicêtre APHP, Paris, France26 Laboratory of immunomonitoring in oncology (L.I.O), UMS 3655 CNRS / US 23 INSERM, GRCC, Villejuif, France.