For patients with cancers that do not respond to immunotherapy drugs, adjusting the composition of microorganisms in the intestines — known as the gut microbiome — through the use of stool, or fecal, transplants may help some of these individuals respond to the immunotherapy drugs, a new study suggests, according to a news release from the National Institutes of Health (NIH).
Researchers at the National Cancer Institute (NCI) Center for Cancer Research, part of NIH, conducted the study in collaboration with investigators from 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 receiving a transplant of fecal microbiota from a patient who had responded to the drug. The results suggest that introducing certain fecal microorganisms into a patient’s colon may help the patient respond to drugs that enhance the immune system’s ability to recognize and kill tumor cells. The findings appear in Science.
“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 study co-leader Giorgio Trinchieri, MD, Chief of the Laboratory of Integrative Cancer Immunology in NCI’s Center for Cancer Research. “Our study is one of the first to demonstrate in patients that altering the composition of the gut microbiome can improve the response to immunotherapy. The data provide proof of concept that the gut microbiome can be a therapeutic target in cancer.”
Changing the gut microbiome may “reprogram” the microenvironments of tumors that resist immunotherapy drugs, making them more favorable to treatment with these medicines, Trinchieri noted.
To test whether fecal transplants are safe and may help patients with cancer better respond to immunotherapy, Trinchieri and his colleagues developed a small, single-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), which were administered 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, the fecal transplants, which were 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 transplants were delivered to the colons of patients through colonoscopies, and each patient also received pembrolizumab.
After these treatments, 6 out of 15 patients who had not originally responded to pembrolizumab or nivolumab responded with either tumor reduction or long-term disease stabilization. One of these patients has exhibited an ongoing partial response after more than two years and is still being followed by researchers, while four other patients are still receiving treatment and have shown no disease progression for over a year.
The investigators analyzed the gut microbiota of all of the patients. The six patients whose cancers had stabilized or improved showed increased numbers of bacteria that have been associated with the activation of immune cells called T cells and with responses to immune checkpoint inhibitors.
The clinical trial was conducted in collaboration with Merck, the maker of pembrolizumab.
