For some cancer patients, a “poop transplant” may promote the positive effects of immunotherapy, a treatment designed to boost the immune system against cancer cells.
Not all cancer patients respond to it immunotherapy drugs. For example, only about 40% of patients with advanced consequences melanoma, a type of skin cancer, benefits from the drugs in the long run recent estimates. Scientists have tried to put the differences between patients who respond well to immunotherapy and those who do not respond to a probable suspect: the microorganisms that live in their intestines.
Now, a new study, published February 4 in the journal Science, contributes to the growing evidence that the right intestinal infection can improve a patient’s response to immunotherapy, helping to stop disease progression or even shrink 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 the drug before. After the transplant, six of the 15 patients responded to immunotherapy for the first time, showing tumor reduction or disease stabilization that lasted longer than a year.
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“The microbes seem to be driving the immunological … changes we see in patients,” said Dr. Hassane Zarour, a cancer immunologist, co-leader of the Cancer Immunology and Immunotherapy Program at Hillman University of Pittsburgh Medical Center and a professor of medicine at the University of Pittsburgh. The team linked the changes in the gut to changes in both the growth of the tumor and the Immune system; for example, some of the participants showed an increase in specific immune cells and antibodies which appeared in their blood.
Despite the positive changes seen in some patients, fecal transplants are unlikely to help all patients whose immunotherapy resists cancer, Zarour said. 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 sifting through the differences between those who improved after the transplant and those who did not.
Intestinal bugs as cancer treatment
The idea for the combination of fecal transplants with immunotherapy first comes from studies in mice with tumors, in which the rodents respond differently to the drugs, depending on the intestinal microbes they carry. according to Science Magazine. By adapting the intestinal microbiome of the mice – the accumulation of bacteria, viruses and other microbes in their digestive tract – scientists found that they could improve this response, but they were not sure which microbes made the difference.
That said, improve mice’s responses to immunotherapy after defecating human cancer patients whose tumors had shrunk under immunotherapy. “When they could take unresponsive mice and give the right bugs … they could turn non-responding mice into responding mice,” Zarour said.
Other research has shown that when human patients used antibiotics, which altered the intestinal microbiome, they were less likely to respond to immunotherapy, providing more evidence that the intestines also make a big difference in humans.
After the positive effects of fecal transplants in mice, scientists began testing the treatment in humans, starting with a few small clinical trials.
In two so trials, led by researchers from Sheba Medical Center in Ramat Gan, Israel, patients received both fecal transplants and oral pills with dried stools. The patients are taking immunotherapy drugs called ‘checkpoint blockers’, which tear off the brakes of immune cells and help boost their activity against tumors. A subgroup of these patients, who had not previously responded to the drugs, suddenly began to respond.
The new study by Zarour and his colleagues reflects these positive results, but it is also beginning to address an important question: How do the intestines strengthen the effects of immunotherapy?
To answer this question, the team examined the microbes found in the donor stool samples and the recipients carefully, before and after fecal transplants. The team also collected blood and tumor cell samples to assess the patients’ immune response over time, and computed tomography (CT) to detect tumor growth. Thereafter, they used artificial intelligence to find connections between all these data points.
Of the 15 patients, nine still did not respond to immunotherapy after their transplant. But of the six who did respond, one showed a complete response to drug blockades, meaning their tumors had shrunk so much that they were no longer observable; two others showed a partial reaction, meaning their tumors shrank but did not disappear, and three showed no disease progression for more than a year. In all six of these patients, the microbes of the donor’s feces rapidly colonized their intestines, and several of the newborn bugs previously linked to positive immunotherapy outcomes increased in number.
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This change in intestinal bacteria elicited an immune response in the six patients as their bodies began to build antibodies that recognized the new defects; these antibodies appear in their blood. Although the link between bacteria-specific antibodies and cancer is not well understood, it is thought that some of these antibodies may help the immune system to target tumor cells, Zarour said.
“The errors that increased in the respondents were really correlated with positive immunological changes,” he said. These patients also built up a larger arsenal of activated T cells – immune cells that can target and kill cancer cells – while 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 numb the effects of immunotherapy; but IL-8 decreased in the six responsive patients.
Links between the gut and the immune system
For comparison, cells that secrete IL-8 increased in the nine patients who did not respond to the fecal transplant. Based on these new data, it appears that IL-8 really does play a critical role in regulating patients’ responses to the two-part treatment, Zarour said.
Compared to the six patients who responded, the nine others also showed less pronounced immune responses to the transplant and lower levels of the observed beneficial bacteria; some even had intestinal microbiome to their fecal donors, suggesting that the bacteria did not take over their intestines, as seen in responsive patients.
Overall, “the gut microbiome may just be one of the many reasons why we do not respond to a specific treatment,” Zarour said. Thus, fecal transplants are not expected to work for everyone. That said, the immune changes seen in the six respondents, including the decrease in IL-8, give hints 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 other cancer patients whose disease is resistant to immunotherapy, Zarour said.
Although small, the new trial provides ‘solid evidence that the manipulation of the microbiome can be beneficial when added to immunotherapy for cancer’, said Dr. Jeffrey Weber, a medical oncologist and co-director of the Melanoma Research Program at Langone Health, New York University, said. who were not involved in the research. Assuming these results hold with other patients, fecal transplants may not be the best way to deliver beneficial microbes into the gut, Weber said in an email.
The future may be in ingesting the bacterium orally after it has been lyophilized, Weber said. This approach may include, for example, something like the oral pills used in other trials. Either that, or scientists can isolate specific metabolites produced by the beneficial bacteria and use them as drugs, Weber said. “The big question is which metabolites of the ‘favorable’ bacterial species are actually responsible for the benefit,” he said.
Originally published on Live Science.