The world's first clinical trial of fecal bacteria to treat cancer has been completed

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The world’s first clinical trial of fecal bacteria to treat cancer has been completed. Is it the future direction?

In the past ten years, the intestinal flora seems to have become a “universal target” in disease treatment, but experts believe that the relevant research is still in its infancy, and the overheated industry should be moderately cooled, and more efforts should be made on weak basic research links.

According to the results of a “world’s first” clinical trial published in “Nature Medicine” this month, scholars from Canada introduced fecal microbiota transplantation (FMT) in the first-line treatment of cancer for the first time, confirming the safety of this therapy in patients with advanced melanoma, and it is expected to improve the response to PD – 1 immunotherapy .

By collecting feces from healthy donors and screening them in the laboratory, the researchers prepared “fecal capsules” for patients to take orally, hoping that the gut flora in the body would be in an optimal state to fight tumors. The results showed that 20% of patients achieved complete tumor remission, and the objective response rate of the entire experimental group reached 65%.

Not only “feces against cancer”, “feces against depression”, “anti-inflammatory bowel disease”, “anti-Alzheimer’s disease”… With the development of microbiome, it seems that all diseases have begun to be related to intestinal flora in the past ten years.

Statistics show that clinical trials of fecal microbiota transplantation in 2021 are widely distributed in the fields of infectious diseases (32.6%) , gastrointestinal tract (23.8%) , dermatology (14.4%) and oncology (12.7%) .

Is it hype or hope? In 2019, “Nature Medicine” commented that microbiome research is booming, and some people have even developed a “smart toilet” that can send fecal bacteria counts to mobile phones. The results now need to be interpreted more cautiously.

Professor Liping Zhao at American Academy of Microbiology and a chair professor at Rutgers University in New Jersey, said that due to the low technical threshold, it is not surprising that fecal microbiology transplants are hot.

“Everyone swarms in, and repeats low-level clinical applications. There are many uneven and even contradictory results, but few people go deep and figure out the basic problems. Therefore, the popularity of fecal microbiota transplants has a negative impact on the healthy development of the entire field.”

The world's first clinical trial of fecal bacteria to treat cancer has been completed. Is it the future direction?

How to evaluate the “fecal cancer” trial?

“Funge against cancer” is one of the key directions in the exploration of disease treatment by fecal microbiota transplantation in recent years.

As early as 2013, preliminary experiments by two research teams from French and American Cancer Institutes found that some cancer treatments rely on gut microbes to activate the immune system.

The academic community has begun to pay attention to the fact that intestinal flora may affect the effect of cancer immunotherapy, including the use of antibiotics, the effect of immunotherapy will become worse, etc., which has contributed to the development of ‘feces anti-cancer’ research.

As a highly malignant tumor, although melanoma accounts for only 1% of skin cancers, it causes more than 80% of patients’ deaths. Until the emergence of immune checkpoint inhibitors such as PD-1, the average survival time of patients with advanced disease has increased to more than 6 years, but there are still a large number of patients who do not respond well to treatment, or develop drug resistance after treatment.

In the aforementioned study, Canadian scholars recruited 20 patients with advanced melanoma. One week before the conventional PD-1 inhibitor (O drug and K drug) treatment, the doctor gave each patient a total of about 40 fecal bacteria capsules, each containing about 80 to 100 mg of fecal preparations from healthy donors, followed by conventional first-line treatment.

The results showed that 4 of the 20 patients had complete remission, 9 had partial remission, and 2 had stable disease for more than 6 months. The objective remission rate and clinical benefit rate were 65% and 75% respectively. This is better than historical data-in the previous CheckMate067 trial, the objective response rate of O drug alone was 44%.

The analysis also found that all patients who received fecal microbiota transplants produced strains with the same intestinal distribution as the donors. Among them, the flora status of those who responded to the treatment was maintained, while those who were ineffective to the treatment, without exception, the intestinal flora returned to the original state over time.

The overall design of this study is relatively complete. It not only explores the clinical effect of fecal microbiota transplantation, but also analyzes some immune factors, and the corresponding animal verification tests have also achieved positive results.

However, the flaws of the study are also obvious. First, the sample size is too small to be convincing.

Secondly, the impact of the time and frequency of administration, the biocompatibility of the intestinal flora between the donor and the recipient, etc. have not been clarified, and the mechanism of action of the colonized strain is also unclear.

In fact, these problems are generally the common situation in the field of fecal bacteria transplantation.

Statistics show that by the end of 2017, about 40,000 cases of fecal microbiota transplantation had been carried out around the world.

In 2019, there were more than 280 clinical research projects of fecal microbiota transplantation registered globally. However, behind the hot business, there are very few clear studies on its mechanism, and there is a lack of high-quality effectiveness data in clinical trials.

In recent years, fecal microbiota transplantation has been directly used in clinical treatment, which is far ahead of basic research. In some diseases, even the causal relationship between intestinal flora and pathogenesis is still unclear, which actually has certain risks.

For example, the aforementioned research does show that fecal microbiota transplantation has a certain prospect in tumor treatment, but it is only a small sample, non-randomized phase I clinical trial. Generally speaking, no matter whether it is anti-cancer or applied to other diseases, I think fecal microbiota transplantation has no way out. Due to the lack of clear targets, it is only a transitional product after all.

Intestinal flora that became a “universal target” overnight

In the past year, two major events have occurred in the field of “fecal transplantation”. First, on November 30 last year, the US FDA approved the first fecal bacteria transplant product RBX2660, which is administered through a catheter enema for patients aged 18 and above with recurrent Clostridium difficile infection. On March 26 this year, the FDA approved SER-109 again for the same indication, which is the first approved oral fecal bacteria capsule.

The approval of the two drugs is considered to be “the ice-breaking of the micro-ecological pharmaceutical track”. For a long time, fecal preparations were not considered medicinal products, and were once regarded as “folk remedies”, and there were also behaviors of speculating celebrity feces at high prices. Until February 2013, fecal microbiota transplantation was written into the treatment guidelines for Clostridium difficile infection (CDI) for the first time , and was named one of the annual “Top Ten Medical Breakthroughs” by Time magazine in November of that year.

At present, the most thorough research on fecal microbiota transplantation is the treatment of Clostridium difficile infection, one of the causes of which is the dysbiosis of the intestinal flora.

But it was also around 2013 that the exploration of indications for fecal microbiota transplantation began to grow rapidly.

Authoritative journals such as Science, Nature, and Cell published relevant research one after another, and the intestinal flora seemed to instantly become a “universal target”.

In the seemingly irrelevant field of autism, after the concept of “gut-brain axis” was proposed, studies have suggested that there are significant differences in the composition of intestinal flora between autistic patients and healthy individuals. Animal experiments have also found that feeding the intestinal bacteria of autistic children to mice induced autistic behavior in mice.

All kinds of papers are growing in a blowout, and they are searched by “gut flora” in “pubmed”. The related research has increased from 248 in 2011 to 8660 in 2021: patients with irritable bowel syndrome have improved defecation function after fecal microbiota transplantation; in patients with metabolic syndrome, some small sample studies suggest that insulin sensitivity increases after fecal microbiota transplantation ; Certain curative effect.

Behind the popularity, researchers believe that one of the reasons is that there is still a lack of suitable treatment options for many diseases.

For example, excessive obesity in metabolic syndrome used to be a very traumatic stomach surgery. Therefore, the academic community hopes to find some low-cost, promising, and safe and effective treatments in practice.

However, except for the recognized treatment of CDI, the efficacy of fecal microbiota transplantation on other diseases is almost controversial, but the degree is different.

The controversy is not just caused by causality. “For example, fecal microbiota transplantation is used to treat chronic immune-mediated diseases.

The etiology of such chronic immune-mediated diseases is complex. It cannot be fully explained by a single intestinal flora imbalance, and it is also difficult to judge the time window for intestinal microorganisms to affect pathology.

It is necessary to be cautious about the “effectiveness” of various results.

It is not uncommon for the curative effect to be unstable after the sample is expanded, and the degree of differentiation between different groups of people is not uncommon.

There are many so-called ‘correlation analyzes’, which show that the flora of patients and healthy people are different. But did the difference cause the disease, or did the disease cause the difference? If you do not continue to study, the results will lose their meaning.

In addition, safety issues have also been put on the table due to the occurrence of accidents. In 2019, a patient with a blood disease in the United States died after being infected with multidrug-resistant E. coli in the stool of a donor after being treated with fecal bacteria capsules. As a result, the US FDA urgently stopped a series of related clinical trials.

Time to ‘cool down’ overheated dung bacteria

Is fecal transplantation a panacea for all diseases, or is it a flash in the pan under the pile of research bubbles?

There is no problem in theory that the intestinal flora as a whole ecosystem will aggravate various diseases after its structure is destroyed.

But in a specific field, what kind of bacteria and what kind of specific disease is caused must be determined through large-scale sequencing and reasonable data analysis combined with mechanistic research.

The current problem is that the strains that really work on different diseases have not been found, so we cannot get rid of the dependence on feces donors. Whether it is directly made of feces as a suspension, or freeze-dried and made into capsules, safety risks and unstable effects are inevitable.

Returning to basic research, the key technologies used in most laboratories are still very rough.

For example, to analyze the data of fecal flora, the most commonly used method is to compare the sequences of known strains in the database with the sequences extracted from feces. However, the research history of intestinal flora is not long.

A large part of the sequences of fecal bacteria represent unknown bacteria, which are not in the database. Researchers cannot classify and determine their functions, and these sequence data are directly discarded. This is a common information loss problem in big data analytics. “If others haven’t studied it, don’t study it, so how to find the real active strain?

“For the same disease, the same “species” or the same “genus”, some articles say that it is positively related to the disease (harmful bacteria) , some say that it is negatively related (beneficial bacteria) , and some say that it is not related. In the final analysis, ‘information distortion’ occurred in the early analysis of big data, and a bunch of errors were superimposed, which eventually led to ‘clinical false impressions’.

There are many similar problems in operation, but almost every paper is repeating the same mistakes.”

Researchers have been advocating analysis methods that do not rely on ready-made databases. Starting from big data itself, artificial intelligence and other technologies can be used to discover patterns.

In the end, it should be the isolation of live bacteria drugs, instead of being satisfied with directly taking fecal preparations and giving them to patients. It is like hitting luck and expecting to have an effect.

Researchers also believe that the current research on intestinal flora is still in the early stage, and more scientific and rigorous critical thinking should be given, and more efforts should be made in weak basic research links.

In the early stage of understanding fecal microbiota transplantation, machine learning and artificial intelligence prediction models can be applied to identify the microbiological characteristics of recipients and donors, thereby predicting the usefulness, outcome and safety of treatment, which will help to develop them as biomarkers and later apply them to personalized diagnosis and treatment.

Researchers pointed out that clinical trials also need more rigorous design, should meet randomized control, and conduct follow-up for several months or years at the same time to investigate the stability and long-term safety of treatment.

In addition, in the future, this field needs to be further explored in terms of ecological theory, including the integration and competition of donor microbes with the patient’s microbes after transplantation, and the interaction with environmental factors such as diet and other lifestyles.

These will determine how fecal bacteria will be used as medicine and administered. Using ecological theory as a guide, I think it will play an important role in the treatment of fecal microbes in the future.

References :

1. https://www.nature.com/articles/d41586-019-01654-0

2. https://www.clinicaltrialsarena.com/comment/microbiome-therapeutics-immuno-oncology-agents/