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Many studies have shown that the intestinal microflora can significantly affect the therapeutic effects of some anti-cancer drugs. However, how should it be developed into therapeutic methods and applied to the clinic to improve the efficacy of anti-cancer drugs?

Bertrand Routy’s reputation in Parisian oncologist circles was not very good in 2015. He was a Ph.D. student in the Gustave Roussy Cancer Center. He often ran from hospital to hospital to collect faecal samples from cancer patients undergoing treatment.

The doctors used him to open up. Routy said: “They are making fun of me and often call me Mr. Caca.”

But after Routy and his colleagues published the research results on Science, no one laughed at him again. At the time, doctors who knew little about gut microbiota research would be very surprised, but until now, these doctors have been very willing to analyze patients’ stool samples in order to be able to predict whether patients will respond to certain anti-neoplastic drugs.

Many diseases seem to have nothing to do with gut microbiota, but in the past few decades, scientists have discovered many diseases related to intestinal microbes, such as depression and obesity. Cancer also has a very close relationship with the intestinal flora because many cancers are actually caused by infectious factors.

And with the widespread use of immunotherapy, scientists have also begun to study the effects of intestinal microbiota on cancer treatment. They tried to elucidate the mechanisms involved and hoped to apply them to the clinic to improve the efficacy of these drugs by manipulating the intestinal flora.

Many people believe that this strategy can revolutionize cancer treatment, but at the same time there are many people who worry that the time is not ripe for applying it to the clinic.

Unexpected association

Although studies on tumor immunotherapy and the relevance of gut microbiota have only begun to increase in the last two or three years, scientists have already begun research on the relationship between gut microbiota and cancer.

For example, in the 1990s scientists discovered the relationship between Helicobacter pylori and gastric cancer. After that, it was also found that some other bacteria are related to the initiation and progression of cancer.

Some microorganisms can activate the body’s inflammatory response, destroy the mucosal layer that prevents pathogens from invading, and create favorable conditions for the growth of certain tumors. Many microorganisms can also promote tumor growth by forcing tumor cells to develop resistance to anticancer drugs.

However, the intestinal microflora may also have a beneficial effect in helping the body fight against tumors. In 2013, the team of Laurence Zitvogel and NCI’s Romina Goldszmid and Giorgio Trinchieri found that the efficacy of some anti-cancer drugs depends largely on the activation of the immune system by intestinal bacteria.

Zitvogel’s team found that the chemotherapeutic drug cyclophosphamide disrupted the intestinal mucosa of patients, allowing bacteria to enter the lymph nodes and spleen, and activate immune cells. The efficacy of the drug is greatly reduced for mice that have no intestinal flora or have been treated with antibiotics.

 

With this discovery, Zitvogel decided to begin research on whether intestinal bacteria will affect the efficacy of checkpoint inhibitors.

Checkpoint inhibitors, including PD-1/L1 and CTLA-4 inhibitors, are capable of relieving the tumor’s suppression of the anti-tumor immune response that has now been approved for the treatment of various cancers. But the problem is that usually only 20-40% of the sick people can respond to the therapy.

In 2015, Zitvogel and his team found that mice that do not contain gut microbiota do not respond to this type of drug, but respond much better to the implantation of a specific bacterium, Bacteroides fragilis.

 

Since then, research in this area has also begun to increase. Thomas Gajewski’s laboratory reported that Bifidobacterium can increase the mouse’s response to tumor immunotherapy drugs. These bacteria present in the intestine can activate the function of immune cells, making them able to fight tumors.

Jeniffer Wargo of the MD Anderson Cancer Center heard some research results in this field at a conference in 2014. After returning to Texas, he began collecting fecal samples from patients with skin cancer undergoing cancer immunotherapy. . In November last year, Wargo, Gajewski and Zitvogel published articles in Science that they found that specific intestinal bacteria are associated with the efficacy of tumor immunotherapy.

 

Samples collected by Routy in Paris also helped Zitvogel analyze that patients treated with antibiotics had a lower response to tumor immunotherapy.

 

Next, the researchers transferred the enterobacteria of the patients involved in the experiment to a mouse model with the same type of tumor. They found that mice that received these “beneficial” bacterial transplants had smaller tumors than those that had not been transplanted.

 

Clinical Trials

At present, researchers are studying whether these research results can be clinically transformed. Hassane Zarour is an immunologist at the University of Pittsburgh. His lab has established a partnership with Merck. Their strategy is to collect fecal samples from patients who respond to checkpoint inhibitors and transplant them into unresponsive patients. This process is called faecal microbiome transplant.

Wargo is also planning a similar clinical study, in collaboration with the Parker Institute for Cancer Immunotherapy and Seres Therapeutics to verify whether fecal transplants can remodel the microbiome of patients who are not responding to checkpoint inhibitors and increase drug responsiveness.

 

The microbial group transplantation method has already been applied in other fields. For example, in February this year, the American Society of Infectious Diseases proposed to use this procedure to treat Clostridium difficile, and Other treatments fail intestinal infections.

 

However, this method also has certain risks. To avoid infecting transplant recipients with harmful pathogenic microorganisms, researchers must carefully select donors and screen graft components prior to transplantation. This is also the strategy that will be adopted by Seres Therapeutics, the Parker Institute and Wargo.

 

Gajewski and his partner Evelo Biosciences have similar strategies. But their clinical trials will test the effect of two tablets containing a single strain on the treatment of different types of cancer including colon cancer and skin cancer.

Zitvogel currently has no plans to conduct clinical trials, but he co-founded a company, EverImmune, to conduct research based on microbiome.

We do not quite understand how microorganisms interact with immunotherapeutic drugs. Some people think that microbes can improve the body’s response to tumors by regulating the ease of activation of the body’s immune system. However, it is still unclear which specific mechanisms include how the bacteria regulate the function of immune cells.

Researchers hope that clinical trial studies can help answer these questions. For example, Wargo is studying bacterial metabolites. Her team is looking for fecal matter in patients and the specific metabolites in the blood that respond to these therapies, and they are also recording patient blood. And the number of immune cells in the tumor.

At present, there are indeed too many unknowns, so some scientists believe that these clinical studies may pose risks to patients. For example, some people involved in clinical trials may experience side effects. Changing the patient’s microbiome may cause them to have other health problems.

There are too many uncertain factors in fecal transplants. This method has been shown to be safe and effective in non-cancer patients. However, there are some side effects of this therapy. For example, one patient has developed obesity after receiving this type of treatment. .

The safety of bifidobacteria that Gajewski plans to use may be higher, because this bacteria has been eaten by humans for thousands of years, and Bifidobacterium can be found in the infant’s intestine, although the number of such bacteria will increase with age. Falling, but at least this bacteria is safe.

The problem is that it is still unclear whether a single type of microorganism can benefit cancer patients. And if a single type of microorganism is effective, what kind of microorganism can be effective?

In a series of articles published last year by Science, even if the same drugs are used, the types of microorganisms that benefit patients in different studies are different for the same type of tumor.

The patient’s diet, sample collection, and data analysis methods may all affect the results of the experiment. If researchers cannot find the reasons for this difference, they are also likely to be unable to interpret the results of clinical trials.

 

Therefore, before the start of clinical trials, these three laboratories should try to repeat the results of different laboratories to find some common beneficial microorganisms.

 

This is probably a common problem in the field of microbiology research. Many studies often prove to be unreliable, or later found that the problem is more complicated than previously thought.

 

Wargo said that this area requires standardization of sample collection and analysis, and validation of the study results in a larger patient population. Since last year, her lab has analyzed fecal samples from more than 500 skin cancer patients receiving different therapies.

 

In the short term, the number of studies in this area will increase. Intestinal microbes do provide new ideas for cancer treatment, but it is still unknown whether these studies can ultimately translate into patient benefits.

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