Science : Clinical trials confirm that stool transplantation enhances the treatment effect of advanced cancer patients

Science: Stool transplantation enhances treatment of advanced cancer patients.  Two clinical trials in cancer patients proved that changing the composition of the gut microbiota can improve immunotherapy response. These data will provide new evidence for the concept of the gut microbiome as a cancer treatment target.

With the continuous advancement of microbial genomics research, human beings have more and more cognition of the microbiota that is symbiotic with themselves-the definition of “human” is far more complicated than imagined. To be precise, humans are super organisms composed of the organic combination of human body and human symbiotic microorganisms.

Intestinal microbes are the main components of human symbiotic microorganisms. Nowadays, a large number of research facts show that gut microbes can affect humans in many aspects, including disease, physical fitness, personality and even lifespan. From this point of view, the interaction between the intestinal flora and the human body is quite complicated. Maybe we can treat certain diseases, such as cancer, by changing the intestinal flora.

On February 4, 2021, researchers from the National Cancer Institute and the Hillman Cancer Center of the University of Pittsburgh published a clinical trial paper titled Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients in Science. .

The clinical trial showed that some patients with advanced melanoma who initially did not respond to immune checkpoint inhibitor therapy did respond to the drug after receiving fecal microbial transplantation (FMT) from patients who responded to the drug.

This means that certain microorganisms may affect the therapeutic effect of cancer immunotherapy. In the future, these microorganisms may be introduced into patients who are not sensitive to immunotherapy, so as to improve the prognosis of these patients.

Human body and gut microbes

We all know that cells are the basic unit that constitutes the human body, and the number of cells in an adult is on the order of tens of trillions. So how many intestinal flora inhabit the human intestine? The answer is ten times that of human cells! Moreover, the composition of the intestinal flora is very complex, and each person carries about 500-1000 different kinds of bacteria in his body.

It is no exaggeration to say that the intestinal flora has become another “you”. As the human body’s largest and most complex microecosystem, the gut microbes themselves and their metabolites can not only regulate human health, but also play an important role as a bridge between diet and host.

Not only that, maintaining a normal intestinal flora is extremely important to human health. Studies have shown that the imbalance of intestinal flora is closely related to diseases such as malnutrition, obesity, diabetes and cancer-the “happy, angry, sad and happy” of intestinal microbes can even affect all aspects of people.

In 2005, Eckburg et al. found through metagenomics research that human intestinal microbes are mainly composed of Firmicutes, Bacteroides, Proteobacteria, and Fusobacterium, among which Bacteroides and Firmicutes are the main dominant flora. It is worth noting that although the composition of human intestinal microbes is very similar, there are great differences in the relative content of microbial groups and strain types among different host individuals.

This also explains to a certain extent why different individuals have different susceptibility to obesity, diabetes, etc., and sensitivity to cancer treatment.

Gut microbes and cancer treatment

The intestine is not only an important digestive organ of the human body, but also the largest immune organ, and the intestinal microbial community settles in the human intestine, so it is not difficult to guess that there may be thousands of threads in the intestinal flora and the immune function of the human body. Wanwi’s connection. In fact, many studies have confirmed this.

On January 6, 2021, researchers from the Sidney Kimmel Comprehensive Cancer Center of Johns Hopkins University in the United States published on Cancer Discovery the title: A pro-carcinogenic colon microbe promotes breast tumorigenesis and metastatic progression and concomitantly activates Notch and βcatenin axes
Research papers.

This study found in mouse models that a microorganism commonly associated with colitis and colon cancer, enterotoxigenic Bacteroides fragilis (ETBF), can colonize the breast and intestines. Researchers have found that these microorganisms can quickly induce breast epithelial hyperplasia and promote the occurrence and metastasis of breast cancer.

Not only that, but studies have shown that the bacterial and viral communities in the intestine can act on the human immune system and have an impact on the effects of chemotherapy and immunotherapy for cancer patients. For example, a previous study found that tumor-bearing mice that did not respond to immunotherapy drugs would begin to respond if they received certain gut microbes in mice that responded to the drugs.

These research phenomena also prompted Dr. Giorgio Trinchieri of the NCI Cancer Research Center and his research team to further explore the impact of the gut microbiota on the prognosis of cancer patients with immunotherapy. Giorgio Trinchieri said that changing the gut microbiota may “reprogram” the microenvironment of tumors, making them more responsive to immunotherapy drugs.

Fecal transplantation helps improve immunotherapy response

In this study, in order to test whether stool transplantation from patients sensitive to immunotherapy can help insensitive patients obtain better immunotherapy effects, the research team developed a small single-arm clinical trial for patients with advanced melanoma (no Controlled single-group test).

The tumors of these patients did not respond to one or more rounds of treatment with immune checkpoint inhibitors, Pembrolizumab or Nivolumab, used alone or in combination with other drugs.

In addition, in order to enhance the safety and rigor of the trial, the researchers analyzed fecal grafts obtained from patients with advanced melanoma who responded to pembrolizumab to ensure that no infectious pathogens would spread. These fecal grafts were diluted with normal saline and transferred into the colon of insensitive patients through a colonoscope, and then these patients who received fecal transplants continued to receive pembrolizumab treatment.

Encouragingly, after receiving stool transplantation, 6 of the 15 patients who initially did not respond to pembrolizumab or nivolumab had tumors that no longer grew or even shrank. One of the patients showed a sustained partial response after more than two years, while the other four patients were still receiving treatment and showed no disease progression for more than a year.

Professor Hassane Zarour, one of the corresponding authors of this study, said: “
In this trial, the patients receiving treatment are very unlikely to have a spontaneous response to the second anti-PD-1 immunotherapy, so any positive response should be attributed to fecal transplantation. “

Although some patients experience minor side effects associated with pembrolizumab, including fatigue, the treatment is well tolerated. The researchers also analyzed the gut microbiota of all patients. The 6 patients whose cancers have stabilized or improved showed an increase in the number of bacteria associated with immune cell T cell activation and immune checkpoint inhibitor response.

In addition, by analyzing the data of proteins and metabolites in these patients, the researchers observed biological changes in patients who responded to fecal transplantation. For example, the level of immune system molecules related to immunotherapy resistance decreases, and the level of biomarkers related to response increases.

Based on the results of these studies, the research team recommends that larger-scale clinical trials should be conducted to further confirm the accuracy of the results and determine relevant biomarkers. These markers may be used to screen those who need fecal transplantation to enhance immunotherapy The effect of cancer patients.

In recent years, the rise of tumor immunotherapy has brought new light to many patients with advanced cancer. However, subsequent clinical studies have shown that some patients are not responsive to immunotherapy, which also hinders tumor immunotherapy to a certain extent. Development and promotion.

This study shows that fecal microbial transplantation may improve the prognosis of patients with advanced cancer who are not sensitive to immunotherapy. Of course, more research is needed to identify those specific microorganisms that are essential to overcome tumor immunotherapy resistance, and to study the biological mechanisms.

In addition, this issue of Science magazine also published a clinical trial paper from the Sheba Medical Center in Israel entitled: Fecal microbiota transplant promotes response in mmunotherapy-refractory melanoma patients.

In this phase 1 clinical trial, 10 patients with anti-PD-1 refractory metastatic melanoma were treated with fecal microbial transplantation (FMT). Among them, 2 patients experienced partial remission and 1 patient experienced complete remission, and tumor cells almost completely disappeared. .

The emergence of tumor immunotherapy represented by PD-1/PD-L1 immune checkpoint inhibitors has changed the pattern of cancer treatment and brought hope to many cancer patients, but there are also many cancer patients who are resistant to immune checkpoint inhibitors. No response to therapy. Therefore, we also need new strategies to help cancer patients who do not respond to immunotherapy.

These two clinical trials in cancer patients proved that changing the composition of the gut microbiota can improve immunotherapy response. These data will provide new evidence for the concept of the gut microbiome as a cancer treatment target.

Reference materials:
https://science.sciencemag.org/content/371/6529/595
https://science.sciencemag.org/content/371/6529/602
https://www.nih.gov/news-events/news-releases/fecal-microbiota-transplants-help-patients-advanced-melanoma-respond-immunotherapy
https://www.upmc.com/media/news/020421-Davar-Zarour-Science
https://cancerdiscovery.aacrjournals.org/content/early/2021/01/05/2159-8290.CD-20-0537.abstract
https://www.eurekalert.org/pub_releases/2021-02/nci-fmt012921.php

Science: Stool transplantation enhances treatment of advanced cancer patients

Science: Stool transplantation enhances treatment of advanced cancer patients

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