HAMBURG, Germany — The human microbiome comprises 39 to 44 billion microbes. That is ten times more than the number of cells in our body. Hendrik Poeck, MD, managing senior physician of internal medicine at the University Hospital Regensburg, illustrated this point at the annual meeting of the German Society for Hematology and Medical Oncology. If the gut microbiome falls out of balance, then “intestinal dysbiosis potentially poses a risk for the pathogenesis of local and systemic diseases,” explained Dr. Poeck.
Cancers and their therapies can also be influenced in this way. said Dr. Poeck.
Microbial diversity could be beneficial for cancer therapy, too. The composition of the microbiome varies significantly from host to host and can mutate. These properties make it a target for precision microbiotics, which involves using the gut microbiome as a biomarker to predict various physical reactions and to develop individualized diets.
Microbiome and Pathogenesis
The body’s microbiome fulfills a barrier function, especially where the body is exposed to an external environment: at the epidermis and the internal mucous membranes, in the gastrointestinal tract, and in the lungs, chest, and urogenital system.
Association studies on humans and experimental manipulations on mouse models of cancer showed that certain microorganisms can have either protective or harmful effects on cancer development, on the progression of a malignant disease, and on the response to therapy.
A Master Regulator?
Disruptions of the microbial system in the gut, as occur during antibiotic therapy, can have significant effects on a patient’s response to immunotherapy. Taking antibiotics shortly before or after starting therapy with immune checkpoint inhibitors (ICIs) significantly affected both overall survival (OS) and progression-free survival (PFS), as reported in a recent review and meta-analysis, for example.
Proton pump inhibitors also affect the gut microbiome and reduce the response to immunotherapy; this effect was demonstrated by an analysis of data from more than 2700 cancer patients that was recently presented at the annual meeting of the European Society for Medical Oncology (ESMO).
The extent to which the gut microbiome influences the efficacy of an ICI or predicts said efficacy was examined in a retrospective analysis published in Science in 2018, which Dr. Poeck presented. Resistance to ICI correlated with the relative frequency of the bacteria Akkermansia muciniphila in the gut of patients with cancer. In mouse models, the researchers restored the efficacy of the PD-1 blockade through a stool transplant.
Predicting Immunotherapy Response
If A muciniphila is present, can the composition of the microbiome act as a predictor for an effective ICI therapy?
Laurence Zitvogel, MD, PhD, and her working group at the National Institute of Health and Medical Research in Villejuif, France, performed a prospective study in 338 patients with non–small cell lung cancer and examined the prognostic significance of the fecal bacteria A muciniphila (Akk). The “Akkerman status” (low Akk vs high Akk) in a patient’s stool correlated with an increased objective response rate and a longer OS, independently of PD-L1 expression, antibiotics, and performance status. The OS for low Akk was 13.4 months, vs 18.8 months for high Akk in first-line treatment.
These results are promising, said Dr. Poeck. But there is no one-size-fits-all solution. No conclusions can be drawn from one bacterium on the efficacy of therapies in humans, since “the entirety of the bacteria is decisive,” said Dr. Poeck. In addition to the gut microbiome, the composition of gut metabolites influences the response to immunotherapies, as shown in a study with ICI.
