How well people respond to cancer drugs apparently also depends on their intestinal flora. A stool transplant could therefore help patients with advanced melanoma for whom immunotherapy was previously ineffective. This is suggested by a pilot study with 15 skin cancer patients. Further studies will have to sound out exactly which bacteria are responsible for the effectiveness of this method. If larger studies are also successful, the approach could open up new treatment options for cancer in the long term.
Some types of cancer inhibit the immune system and thus ensure that the body’s own defenses do not attack them. In immunotherapy, drugs, so-called immune checkpoint inhibitors, are intended to specifically release these “brakes”. These drugs promise a long-lasting effect, but also have a high failure rate: 40 percent of patients with advanced black skin cancer (melanoma) do not respond to them. Studies in mice gave rise to the assumption that the microbiome in the gut also plays a role.
Stool transplant for cancer
Researchers led by Amiran Dzutsev from the National Cancer Institute of the American National Institutes of Health have now followed up on these indications in a pilot study on humans. To do this, they took stool samples from patients who had reacted well to the immune checkpoint inhibitor pembrolizumab, cleaned them up, and administered them to 15 patients who had previously received no immunotherapy.
When they administered pembrolizumab to these patients again after the stool transplantation, six of them showed a clear improvement in their condition: their immune system began to attack the tumor, so that it stopped growing and in some cases even became smaller. “The likelihood that the patients treated in this study would respond spontaneously to a second administration of the drug was very small,” says co-author Hassane Zarour of the University of Pittsburgh. “So every positive reaction should be due to the administration of the fecal transplant.”
Biological changes thanks to new intestinal microbes
To identify the causes of this improvement, the researchers analyzed the intestinal flora of all patients. In fact, they found that the six patients who reacted to the drug after the transplant had an increased number of bacteria that have been linked to the activation of certain immune cells called T cells. Apparently, the change in the intestinal microbiome brought about by the transfer of feces was able to reprogram the immune system so that it can benefit from the medication.
There were also changes in the proteins and metabolic products in the patient’s body: for example, the levels of molecules of the immune system that are associated with resistance to immunotherapy and the levels of biomarkers that are associated with a response decreased , increased.
“In recent years, immunotherapy drugs have helped many patients with certain types of cancer, but we need new strategies to help patients whose cancer does not respond to them,” says Dzutsev’s colleague Giorgio Trinchieri. “Our study is one of the first to show in patients that changing the composition of the gut microbiome can improve response to immunotherapy. The data provide evidence of the concept that the gut microbiome can be a therapeutic target in cancer. “
Which bacteria are the “good”?
In future studies, the researchers hope to gain more insight into which patients can benefit from changes in the gut microbiome. The question of whether the promising results are even confirmed in larger studies is still open. If so, the researchers also want to find out which bacteria are exactly responsible for the positive effect.
“The stool transplant is just a means to an end,” says co-author Diwakar Davar of the University of Pittsburgh. “We know that the composition of the gut microbiome can change the likelihood of responding to immunotherapy. But what are ‘good’ bacteria? There are about 100 trillion gut bacteria and 200 times more bacterial genes in an individual’s microbiome than in all of their cells combined. ”In stool transplants, patients were given a wide range of bacteria, so the right ones were there without being identified .
In the long term, the researchers believe it is conceivable to only administer the helpful bacteria in a targeted manner – and no longer with the help of feces, but simply in tablet form. “We expect that future studies will identify which groups of bacteria in the gut are able to turn patients who do not respond to immunotherapy drugs into patients who do,” said Dzutsev. “If we can find out which microorganisms are critical to immunotherapy response, then it might be possible to deliver those organisms directly to patients who need them without the need for a fecal transplant.”
Source: Amiran Dzutsev (National Cancer Institute of the NIH) et al., Science, doi: 10.1126 / science.abf3363