Intestinal microbes added to the fight against cancer have shown that it seems to affect the efficacy of certain cancer drugs
July 25, 2018 Source: China Science News Author: Tang Yichen
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Certain intestinal bacteria appear to improve people's response to cancer treatment. Doctors also hope that researchers can analyze patients' stool samples to predict whether they will respond to cancer drugs. Image source: Ola Niepsuj
In 2015, Bertrand Routy was a Ph.D. student at the Gustav Roussie Cancer Center in France. He often went to the hospital to collect stool samples from cancer patients. The doctor laughed at him and even gave him a nickname: Mr. Poop.
But after the release of Routy's research results, people stopped ridiculing such research. Studies have shown that certain intestinal bacteria seem to improve people's response to cancer treatment. Doctors also hope that researchers can analyze patients' stool samples to predict whether they will respond to cancer drugs.
Routy, now working at the University of Montreal Health Center in Canada, said: "This is a new world."
The microbiological revolution has affected all aspects of biomedicine, and cancer is one of the revolutionary instruments. In the past few decades, scientists have linked the composition of gut microbes to dozens of seemingly unrelated diseases – from depression to obesity. Cancer and microbes also have a connection: inflammation affects certain tumors, and some types of cancer are infectious. With the development of cancer immunotherapy, scientists are exploring how the intestinal microbiota interacts with these therapies and how to control these effects.
After mice and humans initially found that intestinal bacteria can have an effect on anticancer drugs, scientists began to try to decipher the mechanism. Many clinical trials are testing whether it is possible to manipulate the gut microbiota and improve treatment outcomes.
Some supporters believe that microbiome strategies may change the rules of the game for cancer treatment. "It's very smart," said Jennifer Wargo, a surgeon at the MD Anderson Cancer Center in the United States. But others worry that it is still too early to enter the clinic. William Hanage, an epidemiologist at the Harvard School of Public Health, thinks the idea is "very interesting," but he is concerned about the current beneficial effects on the microbiome.
Interesting relationship
Although research on the effects of microbes on immunotherapy has only appeared in the past three years, the history of exploring the relationship between intestinal bacteria and cancer is not short. In the 1990s, scientists first linked infectious Helicobacter pylori to gastric cancer. Since then, research has also found that other bacteria are involved in the development and progression of cancer. These microbes activate the inflammatory response and destroy the mucus layer, protecting the body from foreign invaders, creating an environment conducive to tumor growth. In addition, they promote cancer cell survival by making cells resistant to cancer drugs.
Gut bacteria can also help fight tumors. In 2013, the Laurence Zitvogel team at the Gustav Roussillon Cancer Center and the National Cancer Institute immunologists Romina Goldszmid and Giorgio Trinchieri found that some cancer treatments rely on the gut microbiota to activate the immune system.
The Zitvogel team found that the chemotherapeutic drug cyclophosphamide disrupted the mucous layer of the intestine, allowing some intestinal bacteria to enter the lymph nodes and spleen and activate specific immune cells. For mice lacking microbes or antibiotics in the body, the drug has largely lost its anticancer effect.
Zitvogel decided to explore whether intestinal bacteria affect the response of immunotherapies such as checkpoint inhibitors. These drugs are usually antibodies that target cell surface molecules such as CTLA4 and PD1, and fight against tumor cells by activating the body's immune system. However, only 20% to 40% of patients respond to checkpoint inhibitors.
In 2015, the Zitvogel team demonstrated that sterile mice did not respond to certain checkpoint inhibitor drugs and that the treatment was improved after giving specific bacteria to the mice.
Thomas Gajewski, a cancer clinician at the University of Chicago in the United States, also pointed out that Bifidobacteria microorganisms increase the response of mice to cancer immunotherapy. These gut bacteria can increase the ability of some immune cells to destroy tumors.
In November 2017, Wargo, Gajewski, and Zitvogel wrote in Science that the positive response to immunotherapy is related to specific gut bacterial species.
To further confirm this association, the researchers transferred the bacteria to a mouse model. The results showed that mice transplanted with "beneficial" bacteria had smaller tumor growth than mice transplanted with bacteria in patients with immunotherapy. “All of these conclusions are very exciting,†said Neeraj Surana, a microbiologist at Boston Children's Hospital. “They offer the possibility to apply microbial science to clinical treatment.â€
Going to the clinic
Researchers are confirming this possibility. Dr. Hassane Zarour, an immunologist at the University of Pittsburgh in Pennsylvania, works with Merck to collect fecal bacteria from patients who respond to checkpoint inhibitor treatment and transfer them to the intestines of non-responders. This process is called Fecal microbial transplantation.
Wargo is also planning a similar test. She collaborated with the Parker Cancer Immunotherapy Institute in San Francisco, USA, and the biotechnology company, Seres Therapeutics, to verify that fecal transplantation can effectively reshape the gut microbiota of non-responders.
In some non-cancer diseases, microbiological transplantation is becoming the mainstream treatment. In February of this year, the American Association of Infectious Diseases recommended the use of this therapy for C. difficile intestinal infection. However, this method has the risk of infecting pathogenic microorganisms, so donor and fecal samples must be carefully screened before transplanting the bacteria to the patient.
At present, the mechanism of interaction between microorganisms and immunotherapy is still unclear. A widely accepted hypothesis is that microbes enhance the body's response to tumors by promoting activation of the immune system. But the exact mechanism, including which bacteria can regulate immune cells, remains a mystery.
Researchers hope that clinical trials will solve this problem. Wargo is studying bacterial metabolites. Her team hopes to find specific metabolic markers that predict the therapeutic effect from the patient's stool and blood, as well as the number of immune cells in the tumor and blood of the participants.
Gajewski believes that microbes may release immune responses by stimulating certain molecules in the gut cells. His team is testing whether circulating immune cell precursors alter their behavior when given to specific bacteria in mice. At the same time, the team is trying to determine what might lead to positive results.
Too early, just right
Given the uncertainty, some scientists believe that testing these methods in humans is risky. Surana said that some trial participants may have side effects. Changing the composition of an individual's microbiome may also lead to other health problems.
There are many unknown factors in stool transplantation. Wargo says it can lead to unexpected results, including weight gain and obesity, "we need to learn from it."
However, it is unclear whether a single strain can help cancer patients, and if so, what bacteria work. Several papers published in the journal Science claim that different bacteria can get better treatment results, even for the same cancers and therapies.
Wargo said the researchers looked at cancer patients in France and the United States, and the diet may explain some of the differences. But Joel Doré, a biologist at the French National Institute of Agriculture, mentioned that differences in sample collection, data analysis and statistical methods may also lead to biased results.
If the researcher cannot find out the cause of these differences, the results of the trial may not be explained. Hanage pointed out that before starting clinical trials, researchers should try to reproduce the results of each other and produce a set of "beneficial" microbes.
This is a common problem in microbiome research. Susan Erdman, a microbiologist and cancer biologist at the Massachusetts Institute of Technology, believes that researchers can make new discoveries by experimenting in different environments.
Wargo also said that hospitals should standardize the methods of collecting samples and analyses, as well as verifying them in larger patient populations.
The researchers are also analyzing patients treated with a combination of two immunotherapies to determine which enteric bacteria can modulate the response to this combination therapy. Wargo hopes that the gut microbiota will eventually help determine which patients will respond to which anticancer treatment. “Can we use it as a biomarker? This is a challenging issue,†she said.
However, scientists will collect more samples. This time, few oncologists will doubt this. Routy said that in the field of cancer treatment, "intestinal microbiology research has changed from being neglected to becoming ultra-popular." Now, no one will laugh at the stool sample collectors, scientists only need to live up to their reputation. (Tang Yichen compiled)
Chinese Journal of Science (2018-07-25 3rd Edition International)
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