The effect of a medicine or the impact of a treatment like chemotherapy does not depend only on your body. The success of a particular drug also depends on the trillions of bacteria in your gut.
The 100 trillion bacteria that live in the human digestive tract – known as the human gut microbiome – help us extract nutrients from food, increase the immune response and modulate the effects of medicines. Recent research, including my own, has implicated the gut microbiome in apparently disconnected states, ranging from response to cancer treatments to obesity and a range of neurological diseases, including Alzheimer’s, Parkinson’s disease, depression, schizophrenia and autism.
What underlies these seemingly discreet observations is the unifying idea that the gut microbiota sends signals beyond the gut and that these signals have broad effects on a wide range of target tissues.
I am an oncologist whose research involves developing new therapies for melanoma. To assess whether altering the microbiome could benefit cancer patients, my colleagues and I evaluated the transfer of fecal matter from patients with melanoma who responded well to immunotherapy for those patients in whom immunotherapy failed. Recently published in the journal Science, our results reveal that this treatment helped to reduce the tumors of patients with advanced melanoma when other therapies did not work.
What connects cancer and intestinal bacteria?
The intestinal microbiota has been associated with the success and failure of several cancer treatments, including chemotherapy and cancer immunotherapy with immune control point inhibitors, such as nivolumab and pembrolizumab. In the most recent studies, the species and relative populations of intestinal bacteria determined the likelihood that a cancer patient would respond to drugs known as “immune checkpoint inhibitors”.
This research showed that differences in the intestinal microbiome between individual patients were associated with several results for these drugs. But the precise mechanisms underlying microbiome-immune interactions remain unclear.
Can faecal microbes help drugs reach difficult-to-treat melanoma?
Oncologists often treat patients with advanced melanoma using immunotherapies targeting specific proteins on the surface of immune cells known as PD-1 and CTLA-4. However, they work on a subset of patients – 50% -70% of patients have cancers that get worse despite treatment. No medical treatment has been approved to treat melanoma patients who have failed PD-1 immunotherapies.
To investigate whether certain types of microbes could increase the effectiveness of PD-1 immunotherapies, my colleagues and I developed a study in which we collected fecal microbes from patients who responded well to this therapy and administered them to cancer patients who did not benefit from the drugs the checkpoint.
We chose feces from patients who responded well to immunotherapy based on the hunch that they would have greater amounts of bacteria involved in helping to reduce cancer. As it is difficult to identify one or two species of bacteria responsible for the beneficial response to these therapies, we use the entire bacterial community – hence the fecal microbe transplant.
The transplant recipients were patients whose melanoma never responded to immunotherapy. Both recipients and donors underwent disease screening to ensure that no infectious agents were transmitted during the transplant. After a biopsy of their tumor, patients received a fecal microbe transplant from patients who benefited from immunotherapy along with a drug called pembrolizumab, which was continued every three weeks.
My colleagues and I evaluated the fecal microbe transplant 12 weeks after treatment. Patients whose cancers decreased or remained the same size after transplanting a fecal microbe continued to receive pembrolizumab for up to two years.
Results of a new clinical trial
After this fecal microbe transplant treatment, the tumors of six out of 15 patients in the study had tumors that either decreased or remained the same. The treatment was well tolerated, although some of the patients experienced minor side effects, including fatigue.
When we analyzed the intestinal microbiota of the treated patients, we found that the six patients whose cancers had stabilized or improved showed an increase in the number of bacteria that had previously been associated with responses to immunotherapy.
My colleagues and I also analyzed the blood and tumors of the responders. In doing so, we found that respondents had lower levels of adverse immune cells, called myeloid cells, and higher levels of immune memory cells. In addition, when analyzing proteins in the blood serum of treated patients, we observed reductions in the levels of the main molecules of the immune system associated with resistance in responders.
These results suggest that the introduction of certain intestinal microorganisms into a patient’s colon can help the patient respond to drugs that increase the immune system’s ability to recognize and kill tumor cells.
Ultimately, we hope to move beyond fecal microbial transplants to specific collections of microbes in cancers other than melanoma, paving the way for standardized microbial-based drug therapy to treat tumors resistant to immunotherapy.
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This article was republished from The Conversation, a nonprofit news site dedicated to sharing ideas from academic experts. It was written by: Diwakar Davar, Pittsburgh University.
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Diwakar Davar receives research funding from Arcus Biosciences, BristolMyersSquibb (BMS), Checkmate Pharmaceuticals, CellSight Technologies, Merck, GlaxoSmithKline (GSK). Diwakar Davar receives consulting fees from Checkmate Pharmaceuticals, Shionogi, Vedanta Biosciences.