Humans carry around trillions of microbes, and the ones in our guts - the gut microbiome - play an essential role in our health. Researchers have been learning more about the many connections between human health, disease, and gut bacteria. Work has shown that these gut microbes can affect how medications are metabolized. Some research has suggested that the composition of the microbiome may be connected to how well cancer treatment works.
Now scientists have determined that if immunotherapy is not working for a patient, it might work better if an alteration is made to their gut microbiome. This could be accomplished by transplanting feces from healthy donors to these patients (in a clinical setting). The findings have been reported in Science.
In this work, the investigators assessed advanced melanoma patients who had not responded to treatment with a type of immunotherapy called an immune checkpoint inhibitor. These drugs are supposed to work by releasing a brake that stops the immune system from attacking cancer cells.
The researchers created safe fecal transplants from volunteers with advanced melanoma who responded positively to an immune checkpoint inhibitor called pembrolizumab. These transplants were delivered (through colonoscopies) to advanced melanoma patients that had not responded to immune checkpoint inhibitor treatment. Six of fifteen patients that had not seen any effect from these drugs began to see their tumors shrink, or their disease stabilize after the transplant. There were some minor side effects associated with pembrolizumab, but four of the now-responsive patients have not shown disease progression for more than a year, and one has been responding partially for over two years.
"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 co-leader Giorgio Trinchieri, M.D., chief of the Laboratory of Integrative Cancer Immunology at the National Cancer Institute's (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."
Trinchieri added that more research will be needed to figure out which bacteria enabled the patient to overcome the drug resistance, and exactly how that happened.
Previous work has indicated that changing the microbiome in a mouse model can improve how well immunotherapy works. The gut microbiome may be affecting tumor microenvironments, suggested Trinchieri.
The scientists also found that there were increased numbers of bacteria that are linked to T cell activation and immune checkpoint response in the patients whose diseases had stabilized or improved. There was also a reduction in the level of biomarkers that have been linked to immunotherapy resistance, and an increase in those linked to immunotherapy response.
The researchers are hopeful that these results will promote larger clinical trials to confirm the findings, identify other biomarkers, and find candidate patients.
"We expect that future studies will identify which groups of bacteria in the gut are capable of converting patients who do not respond to immunotherapy drugs into patients who do respond," said study co-first author Amiran Dzutsev, M.D., Ph.D., of NCI's Center for Cancer Research. "These could come from patients who have 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 requiring a fecal transplant," he added.