News release
Thursday, February 4, 2021
For patients with cancers that do not respond to immunotherapy drugs, adjusting the composition of microorganisms in the gut – known as the gut microbiome – through the use of stool or fecal transplants can help some of these individuals respond to the immunotherapy drugs, new study suggests. Researchers from the National Cancer Institute (NCI) Center for Cancer Research, 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, did respond to the drug after transplanting fecal microbiota from a patient who had responded to the drug. The results suggest that introducing certain fecal microorganisms into a patient’s colon can help the patient respond to drugs that boost the immune system to recognize and kill tumor cells. The findings appeared in Science on February 4, 2021.
“In recent years, many patients with certain types of cancer have benefited from immunotherapy drugs called PD-1 and PD-L1 inhibitors, but we need new strategies to help patients whose cancers do not respond,” said co-leader of the study Giorgio Trinchieri, MD, head of the Laboratory for Integrative Cancer Immunology at NCI’s Center for Cancer Research. “Our study is one of the first to show in patients that changing the composition of the gut microbiome can improve response to immunotherapy. The data provides a proof of concept that the gut microbiome may be a therapeutic target in cancer. “
More research is needed, added Dr. Trinchieri, to identify the specific microorganisms crucial to overcome a tumor’s resistance to immunotherapy drugs and to investigate the biological mechanisms involved.
Research suggests that communities of bacteria and viruses in the gut can affect the immune system and response to chemotherapy and immunotherapy. For example, previous studies have shown that tumor-bearing mice that do not respond to immunotherapy drugs can respond if they receive certain gut microorganisms from mice that responded to the drugs.
Altering the gut microbiome can “reprogram” the microenvironments of tumors that resist immunotherapy, making them more favorable for treatment with these drugs, Dr. Trinchieri on.
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. The patients’ tumors had not responded to one or more rounds of treatment with the immune checkpoint inhibitors pembrolizumab (Keytruda) or nivolumab (Opdivo), given alone or in combination with other drugs. Immune checkpoint inhibitors release a brake that keeps 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, the fecal grafts were delivered into the colonoscopies of patients and each patient also received pembrolizumab.
Following these treatments, 6 of 15 patients who originally did not respond to pembrolizumab or nivolumab responded with either tumor reduction or long-term disease stabilization. One of these patients showed a sustained partial response after more than two years and is still being monitored by investigators, while four other patients are still on treatment and have not shown disease progression for over a year.
The treatment was well tolerated, although some patients experienced mild side effects associated with pembrolizumab, including fatigue.
The researchers analyzed the gut microbiota of all patients. The six patients whose cancer had stabilized or improved showed increased bacteria counts associated with the activation of immune cells called T cells and 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 response increased.
Based on the findings of the study, the researchers suggest larger clinical trials should be conducted to confirm the results and identify biological markers that could ultimately be used to select patients most likely to benefit from treatments that alter the gut microbiome .
“We expect that future studies will reveal which groups of bacteria in the gut are able to convert patients who do not respond to immunotherapy drugs into those who do,” said Amiran Dzutsev, MD, Ph.D., of NCI’s Center for Health. Cancer Research, co-lead author of the study. “These can come from patients who have responded or from healthy donors. If researchers can identify which microorganisms are critical to the response to immunotherapy, 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 conducted in collaboration with Merck, the maker of pembrolizumab.
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