Press release
Thursday, February 4, 2021
For cancer patients who do not respond to immunotherapy drugs, adjusting the composition of microorganisms in the intestine (known as the intestinal microbiome) by using feces or feces, transplants can help some of the these individuals to respond to immunotherapy drugs. suggests a new study. Researchers from the National Cancer Institute’s (NCI) Cancer Research Center, which is part of the National Institutes of Health, conducted the study in collaboration with researchers from 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 had response to medication. The results suggest that the introduction of certain fecal microorganisms into the patient’s colon may help the patient respond to drugs that improve 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 cancer patients who do not respond,” he said. study director, Giorgio Trinchieri, MD, head of the Integrative Cancer Immunology Laboratory at the NCI Cancer Research Center. “Our study is one of the first to show in patients that altering the composition of the intestinal microbiome can improve the response to immunotherapy. The data provide evidence of the concept that the intestinal microbiome can be a therapeutic target in cancer.
More research is needed, added Dr. Trinchieri, to identify specific microorganisms that are critical to overcome a tumor’s resistance to immunotherapeutic drugs and to investigate the biological mechanisms involved.
Research suggests that bacterial and virus communities 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 drugs with immunotherapy can begin to respond if they receive certain intestinal microorganisms from mice that responded to the drugs.
Changing the gut microbiome can “reprogram” the microenvironments of tumors that resist immunotherapeutic drugs, making them more favorable to treatment with those drugs, Dr. Trinchieri noted.
To test whether fecal transplants are safe and can help cancer patients respond better to immunotherapy, Dr. Trinchieri and colleagues developed a small one-arm clinical trial for patients with advanced melanoma. Patients ’tumors had not responded to one or more rounds of treatment with pembrolizumab (Keytruda) or nivolumab (Opdivo) immune checkpoint inhibitors, which were administered alone or in combination with other drugs. Inhibitors of immune checkpoints release a brake that prevents the immune system from attacking tumor cells.
In the study, fecal transplants obtained from patients with advanced melanoma who had 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 both patients ’points by colonoscopies and each patient also received pembrolizumab.
Following these treatments, 6 out of 15 patients who had not originally responded to pembrolizumab or nivolumab responded with tumor reduction or long-term disease stabilization. One of these patients has shown a continuous partial response after more than two years and researchers are still following him, while four other patients continue to receive treatment and have not shown disease progression for more than a year.
Treatment was well tolerated, although some of the patients experienced minor side effects that were associated with pembrolizumab, including fatigue.
The researchers analyzed the intestinal microbiota of all patients. The six patients whose cancers had stabilized or improved showed a higher number of bacteria that were associated with the activation of immune cells called T cells and with responses to immune checkpoint inhibitors.
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, the levels of immune system molecules associated with resistance to immunotherapy decreased and the levels of biomarkers associated with the response 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 more likely to benefit from treatments. which 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 respond,” said Amiran Dzutsev, MD, Ph.D., of NCI’s Center for Cancer Research, co-author of the study. “They could come from patients who have responded or from healthy donors. If researchers can identify which microorganisms are critical for the response to immunotherapy, it may be possible to deliver these organisms directly to patients who need them, without the need for a stool transplant, ”he added.
The clinical trial was conducted in collaboration with Merck, the manufacturer of pembrolizumab.
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