Gut microbiome influences efficacy of immunotherapy
Gut microbiome influences efficacy of immunotherapy
- The effect of the gut microbiome on cancer immunotherapy is an emerging field
- The composition of the gut microbiome affects clinical outcomes in cancer, including survival
- Researchers are looking at ways to alter the gut microbiota to improve patients’ clinical outcomes
The composition of gut microbiome has a major impact on the efficacy of immunotherapies and can significantly affect survival of patients with cancer. Dr Meriem Messaoudene, Postdoctoral Researcher, University of Montreal Research Center, Montreal, Canada, presented the latest research at the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 2019, Amsterdam, the Netherlands.
This relatively new field of research emerged in 2011. The discovery of immune checkpoint blockers, such as CTLA-4 and PD-1 blockers has revolutionised cancer treatment and led to unprecedented increases in overall and progression-free survival.
“Despite these impressive results, 70% of patients develop resistance to immune checkpoint blockers,” explained Dr Messaoudene. “Some of these resistance mechanisms are already known.”
Factors that may lead to resistance to cancer immunotherapies include mutational load, radiation therapy and loss of interferon-gamma signalling.
“Predictive markers for resistance are urgently needed,” said Dr Messaoudene.
Several published studies have demonstrated an epidemiological association between gut microbiota composition and cancer outcomes.
Dr Messaoudene’s lab (led by Dr Jean-Pierre Routy) has pioneered research into the link between gut microbiota and the efficacy of cancer immunotherapy.
She showed that when mice with non-small cell lung cancer (NSCLC) were treated with antibiotics, either 2 months before and/or 1 month after the first administration of a PD-1 inhibitor, median overall survival was significantly reduced.
“The anti-tumour efficacy of immune checkpoint blockades requires gut bacteria,” she explained. The negative effect on survival was more marked when mice were given antibiotics before PD-1 inhibitor treatment.
The same effect has been shown in human patients. A retrospective study of 175 patients treated with PD-1 inhibitors for advanced renal cell carcinoma (RCC), urothelial cancer (UC) and NSCLC examined the effects of antibiotic use 2 months before and within the first month of immunotherapy.
51 (29%) received antibiotics (ATB+ group). This group had a significantly shorter progression-free and overall survival when compared to the antibiotic-free (ATB-) group: 3.4 versus 5.2 months (p<0.013) and 12.2 versus 20.8 months (p<0.001), respectively.
The overall survival was 7.0 versus 13.8 months (p<0.038) in the ATB+ and ATB- NSCLC groups, respectively. In patients with RCC and UC, the ATB+ group had a shorter progression-free survival when compared to the ATB- group (4.3 vs 7.4 months, p<0.013 and 1.8 vs 4.3 months, p=0.048, respectively). The negative impact of antibiotics was maintained after multivariate analyses adjusting for risk factors in each tumour type.
At least 12 other studies in over 1,800 patients have confirmed the negative effect of antibiotic treatment on patient outcomes in a variety of cancers.
In another study, Dr Messaoudene showed that faecal microbiota transplantation (FMT) from cancer patients who responded to immune checkpoint blockers into germ-free or antibiotic-treated mice improved the anti-tumour effect of PD-1 inhibitor treatment; however, FMT from non-responding patients failed to do so.
Metagenomic profiles of patient stool samples at diagnosis also revealed a correlation between clinical responses to PD-1 inhibitor treatment and the abundance of Akkermansia muciniphila in the gut.
In this study, oral supplementation with A. muciniphila after FMT with non-responder faeces restored the efficacy of the PD-1 blockade in an interleukin-12-dependent manner by increasing the recruitment of T lymphocytes into mouse tumour beds.
Other research from Dr Messaoudene’s group is looking at how factors such as diet and probiotic supplements can affect the activity of immune checkpoint blocker treatment.
There is now an international consortium of about 25 centres who are combining efforts to better understand the role of gut microbiota in cancer. These centres are gathering microbial genomic samples and looking at ways to improve gut microbiota, with the aim of improving patient outcomes.
Dr Messaoudene concluded her talk by saying, “The gut microbiome is a novel element that needs to be included in personalised medicine studies. Antibiotics blunt the efficacy of PD-1 inhibitors and should be considered as a risk factor for resistance in patients receiving immunotherapy.” She added “this research has led to a novel approach to treating cancer patients in 2019; however, the mechanisms still remain elusive”.
Based on Messaoudene M. How gut microbiome influences efficacy of immunotherapy (symposium S0614). Presented on Sunday 14 April 2019.
- Derosa L, Routy R et al. Antibiotics prescription to decrease progression-free survival (PFS) and overall survival (OS) in patients with advanced cancers treated with PD1/PDL1 immune checkpoint inhibitors. Journal of Clinical Oncology 2017;35(15_suppl): 3015-3015
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