Press release
Thursday, February 4, 2021
For cancer patients who do not respond to immunotherapy drugs, adjusting the composition of intestinal microorganisms – known as the intestinal microbiome – through the use of stool or feces, transplants can help some of these individuals respond to immunotherapy drugs. a new study suggests. Researchers at the National Cancer Institute (NCI) Cancer Research Center, which is part of the National Institutes of Health, conducted the study in collaboration with investigators at the UPMC Hillman Cancer Center at the University of Pittsburgh.
In the study, some patients with advanced melanoma who initially did not respond to treatment with an immune checkpoint inhibitor, a type of immunotherapy, responded to the drug after receiving a fecal microbiota transplant from a patient who responded to drug. The results suggest that the introduction of certain fecal microorganisms into a patient’s colon may help the patient respond to drugs that increase the immune system’s ability to recognize and destroy tumor cells. The discoveries appeared in Science on February 4, 2021.
“In recent years, immunotherapeutic drugs called PD-1 and PD-L1 inhibitors have benefited many patients with certain cancers, but we need new strategies to help patients whose cancers do not respond,” said the co-leader. study, Giorgio Trinchieri, MD, head of the Laboratory of Integrative Cancer Immunology at the NCI Center for Cancer Research. Our study is one of the first to demonstrate in patients that changing the composition of the intestinal microbiome can improve the response to immunotherapy. The data provide evidence of the concept that the intestinal microbiome may be a therapeutic target in cancer. ”
More research is needed, Dr. Trinchieri added, to identify specific microorganisms that are critical for overcoming a tumor’s resistance to immunotherapeutic drugs and to investigate the biological mechanisms involved.
Research suggests that communities of bacteria and viruses in the gut may affect the immune system and its response to chemotherapy and immunotherapy. For example, previous studies have shown that mice carrying tumors that do not respond to immunotherapeutic drugs can begin to respond if they receive certain intestinal microorganisms from mice that have responded to drugs.
Changing the gut microbiome can “reprogram” the microenvironments of tumors that resist immunotherapeutic drugs, making them more favorable to treatment with these drugs, Dr. Trinchieri noted.
To test whether fecal transplants are safe and can help cancer patients respond better to immunotherapy, Dr. Trinchieri and colleagues have developed a small, one-arm clinical trial for patients with advanced melanoma. Patients’ tumors did not respond to one or more rounds of treatment with pembrolizumab (Keytruda) or nivolumab (Opdivo) immune checkpoint inhibitors, which were given alone or in combination with other medicines. Immune checkpoint inhibitors release a brake that prevents the immune system from attacking tumor cells.
In the study, fecal transplants, which were obtained from patients with advanced melanoma who responded to pembrolizumab, were analyzed to ensure that no infectious agents would be transmitted. After treatment with saline and other solutions, fecal transplants were delivered to patients’ colonies by colonoscopy and each patient also received pembrolizumab.
Following these treatments, 6 out of 15 patients who did not initially respond to pembrolizumab or nivolumab responded with either tumor reduction or long-term stabilization of the disease. One of these patients had a partially continuous response after more than two years and is still being followed by researchers, while four other patients are still receiving treatment and have not shown disease progression for more than a year.
Treatment was well tolerated, although some of the patients had minor side effects that were associated with pembrolizumab, including fatigue.
The investigators analyzed the intestinal microbiota of all patients. The six patients whose cancers stabilized or improved showed an increased number of bacteria that were associated with the activation of immune cells called T cells and with responses to inhibitors of the immune control point.
In addition, by analyzing data on proteins and metabolites in the body, the researchers observed biological changes in patients who responded to the transplant. For example, levels of immune system molecules that are associated with resistance to immunotherapy have decreased, and levels of biomarkers that are associated with the response have increased.
Based on the results of the study, the researchers suggest that larger clinical trials should be conducted to confirm the results and identify biological markers that could eventually be used to select patients who are most likely to benefit from treatments that alter the gut microbiome.
“We expect future studies to identify which groups of gut bacteria are able to turn patients who do not respond to immunotherapeutic drugs into patients who respond,” said Amiran Dzutsev, MD, Ph.D., of NCI’s Center for Cancer Research. , co-author of the study. These could come from responding patients or from healthy donors. If researchers can identify which microorganisms are critical for the response to immunotherapy, then it may be possible to deliver these organisms directly to patients who need them, without requiring a fecal transplant, ”he added.
The clinical trial was conducted in collaboration with Merck, the manufacturer of pembrolizumab.
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