For some cancer patients, a “poop transplant” can increase the positive effects of immunotherapy, a treatment designed to strengthen the immune system against cancer cells.
Not all cancer patients respond to Immunotherapy drugs. For example, only about 40% of patients with advanced diseases melanoma, a type of skin cancer, obtains long-term benefits from the drugs, according to recent estimates. In an attempt to identify the differences between patients who respond well to immunotherapy and those who do not, scientists have focused on a likely suspect: the microorganisms that live in their bowels.
Now, a new study, published on February 4 in the journal Science, adds to the growing evidence that having the right intestinal insects can improve a patient’s response to immunotherapy, helping to halt disease progression or even reduce tumors.
In the study, scientists collected feces from melanoma patients who responded well to immunotherapy and then transplanted their feces (and microbes) into the intestines of 15 patients who had never responded to medications. After transplantation, six of the 15 patients responded to immunotherapy for the first time, presenting a tumor reduction or stabilization of the disease that lasted more than a year.
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“Microbes really seem to drive the immune changes we see in patients,” said study author Dr. Hassane Zarour, a cancer immunologist, co-leader of the Cancer Immunology and Immunotherapy Program at the University of Pittsburgh’s Hillman Medical Center and professor of medicine at the University of Pittsburgh. The team linked changes in intestinal insects to changes in tumor growth Imune system; for example, some of the participants showed an increase in specific immune cells and antibodies that appeared in your blood.
Despite the positive changes seen in some patients, fecal transplants are unlikely to help all patients whose cancer resists immunotherapy, said Zarour. In the new study, for example, nine of the 15 patients did not benefit from the treatment. As part of their research, the team began to examine the differences between those who improved after the transplant and those who did not.
Intestinal insects as a cancer treatment
The idea of combining fecal transplants with immunotherapy came from studies in mice with tumors, in which rodents responded differently to drugs depending on which intestinal microbes they carried according to the journal Science. By adjusting the mice’s intestinal microbiomes – the collection of bacteria, viruses and other microbes in their digestive tracts – the scientists found that they could improve that response, but were unsure which microbes made the difference.
Said that, the rats’ responses to immunotherapy improved after receiving fecal matter from human cancer patients whose tumors had shrunk with immunotherapy. “When they took mice that didn’t respond and gave them the right insects … they were able to convert mice that didn’t respond into mice that responded,” said Zarour.
Other research has shown that when human patients take antibiotics, which alter the intestinal microbiome, they are less likely to respond to immunotherapy, providing more evidence that intestinal insects also make a big difference in people.
Having seen the positive effects of fecal transplants in mice, the scientists began to test the treatment in humans, starting with some small clinical trials.
In two such essay, led by researchers at Sheba Medical Center in Ramat Gan, Israel, patients received fecal transplants and oral pills containing dry stools. The patients then took immunotherapy drugs called “checkpoint blocks,” which essentially pull the brakes off immune cells and help amplify their activity against tumors. A subset of these patients, who previously did not respond to medications, suddenly started to respond.
The new study by Zarour and his colleagues echoes these positive results, but it also begins to address a crucial question: Like Do intestinal insects increase the effects of immunotherapy?
To answer this question, the team closely analyzed the microbes present in the stool samples from donors and recipients, before and after fecal transplants. The team also collected blood samples and tumor cells to assess patients’ immune responses over time, and computed tomography (CT) scans to monitor tumor growth. They then used artificial intelligence to find connections between all of these data points.
Of the 15 patients, nine have not yet responded to immunotherapy after transplantation. But of the six who responded, one showed a complete response to checkpoint blocking medications, which means that his tumors have shrunk so much that they are no longer detectable; two others showed a partial response, meaning that their tumors subsided but did not disappear, and three showed no progression of the disease for more than a year. In all six of these patients, microbes from the donor’s feces quickly colonized their intestines, and several of the new insects that were previously linked to positive immunotherapy results increased in number.
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This change in intestinal bacteria triggered an immune response in the six patients, as their bodies began to build antibodies that recognized the new insects; these antibodies appeared in your blood. While the link between specific antibodies to bacteria and cancer is not well understood, it is believed that some of these antibodies may help prepare the immune system to hunt for tumor cells, said Zarour.
“The bugs that increased in the responders were actually correlated with positive immunological changes,” he said. These patients also built a larger arsenal of activated T cells – immune cells that can attack and kill cancer cells – while the substances that suppress the immune system decrease. For example, a protein called interleukin-8 (IL-8) can summon immunosuppressive cells to tumor sites and, therefore, mitigate the effects of immunotherapy; but IL-8 decreased in the six responsive patients.
Links between the intestine and the immune system
By comparison, cells that secrete IL-8 increased in the nine patients who did not respond to fecal transplantation. Based on this new data, “IL-8 does appear to play a critical role in regulating patient responses” to treatment in two parts, said Zarour.
In comparison with the six responsive patients, the other nine also showed less pronounced immune responses to transplantation and lower levels of the beneficial bacteria observed; some even had intestinal microbiomes different from those of their fecal donors, suggesting that the bacteria did not take over their intestines as seen in responsive patients.
In general, “the intestinal microbiome may be just one of many reasons why we don’t respond to a specific treatment,” said Zarour, so fecal transplants are not expected to work for everyone. That said, the immune changes seen in the six patients who responded, including the decline in IL-8, provide clues as to why it works for some people.
In the future, these results will need to be validated in larger groups of melanoma patients, as well as in other cancer patients whose disease resists immunotherapy, said Zarour.
Although small, the new trial provides “firm evidence that manipulating the microbiome can yield benefits when added to cancer immunotherapy,” said Dr. Jeffrey Weber, medical oncologist and co-director of Langone University’s Melanoma Research Program. New York Health, which was not involved in the research. Assuming these results hold up in other patients, fecal transplants may not be the best way to inject useful microbes into the intestine, Weber said in an email.
The future may lie in ingesting the bacteria orally after freeze-dried, Weber said. This approach may include something similar to oral pills used in other studies, for example. Either that, or scientists could isolate specific metabolites produced by useful bacteria and use them as drugs, said Weber. “The big question is, which metabolites of the ‘favorable’ bacterial species are really responsible for the benefit,” he said.
Originally published on Live Science.