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.