Press release
Thursday, February 4, 2021
For cancer patients who do not respond to immunotherapy drugs, adjusting the composition of microorganisms in the intestines – known as the intestinal microbiome – through the use of faeces or stools, transplants can help some of these individuals respond to immunotherapy drugs, the new study suggests. Researchers at the Cancer Research Center at the National Cancer Institute (NCI), part of the National Institutes of Health, conducted the study in collaboration with researchers 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 immunological control point inhibitor, a type of immunotherapy, responded to the drug after receiving a fecal microbiota transplant from a patient who responded to the 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 kill tumor cells. The findings appeared in Science on February 4, 2021.
“In recent years, immunotherapy drugs called PD-1 and PD-L1 inhibitors have benefited many patients with certain types of cancer, but we need new strategies to help patients whose cancers do not respond,” said the study’s co-leader. , Giorgio Trinchieri, MD, head of the Integrative Cancer Immunology Laboratory at NCI’s 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 proof of concept that the intestinal microbiome may be a therapeutic target in cancer. “
More research is needed, added Dr. Trinchieri, to identify specific microorganisms that are critical to overcoming a tumor’s resistance to immunotherapy drugs and to investigate the biological mechanisms involved.
The research suggests that communities of bacteria and viruses in the intestines may affect the immune system and its response to chemotherapy and immunotherapy. For example, previous studies have shown that tumor mice that do not respond to immunotherapy drugs can begin to respond if they receive certain intestinal microorganisms from mice that responded to the drugs.
Changing the intestinal microbiome can “reprogram” tumor microenvironments that resist immunotherapy drugs, making them more favorable to treatment with these drugs, noted Dr. Trinchieri.
To test whether fecal transplants are safe and can help cancer patients respond better to immunotherapy, Dr. Trinchieri and his colleagues developed a small, single-arm clinical trial for patients with advanced melanoma. The patients’ tumors did not respond to one or more rounds of treatment with the immunological control point inhibitors pembrolizumab (Keytruda) or nivolumab (Opdivo), which were administered alone or in combination with other drugs. Immune control point inhibitors release a brake that prevents the immune system from attacking tumor cells.
In the study, fecal transplants, 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 the patients’ colon through colonoscopies, and each patient also received pembrolizumab.
After these treatments, 6 out of 15 patients who did not originally respond to pembrolizumab or nivolumab responded with tumor reduction or long-term stabilization of the disease. One of these patients showed a continuous partial response after more than two years and is still being followed by researchers, while another four patients are still receiving treatment and have not shown disease progression for more than a year.
The treatment was well tolerated, although some of the patients had minor side effects that were associated with pembrolizumab, including fatigue.
The researchers analyzed the intestinal microbiota of all patients. The six patients whose cancers stabilized or improved showed an increase in the number of bacteria that were associated with the activation of immune cells called T cells and with responses to immune checkpoint inhibitors.
In addition, when analyzing data on proteins and metabolites in the body, the researchers observed biological changes in patients who responded to the transplant. For example, the levels of immune system molecules associated with resistance to immunotherapy have decreased and the levels of biomarkers 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 intestinal microbiome.
“We hope that future studies will identify which groups of bacteria in the gut are able to convert patients who do not respond to immunotherapy drugs into patients who do,” said Amiran Dzutsev, MD, Ph.D., of the Cancer Center at NCI Research, co. – first author of the study. “This can come from patients who responded 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 the need for a fecal transplant, ”he added.
The clinical trial was carried out in collaboration with Merck, the manufacturer of pembrolizumab.
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