The effect of a drug, or the impact of a treatment such as chemotherapy, does not just depend on your body. The success of a particular medicine also depends on the trillions of bacteria in your gut.
The 100 billion bacteria that live in the human digestive tract – known as the human gut microbiome – help us to extract nutrients from food, increase the immune response and modulate the effects of drugs. Recent research, including my own, has implicated the gut microbiome in seemingly unrelated conditions, ranging from the response to cancer treatment to obesity and a number of neurological diseases, including Alzheimer’s, Parkinson’s disease, depression, schizophrenia, and autism.
Underlying these seemingly discrete observations is the unifying idea that the gut microbiota sends signals outside the gut and that these signals have broad effects on a large amount of target tissues.
I am a medical oncologist with the development of new therapies for melanoma. To evaluate whether the change in the microbiome could benefit cancer patients, my colleagues and I evaluated the transfer of feces from melanoma patients who respond well to immunotherapy to the patients for whom immunotherapy has failed. Our results, recently published in the journal Science, show that this treatment helped shrink the tumors of advanced melanoma patients when other treatments did not work.
What connects cancer and intestinal bacteria?
The intestinal microbiota has been linked to the success and failure of multiple cancer treatments, including chemotherapy and cancer immunotherapy with immune control inhibitors such as nivolumab and pembrolizumab. In the more recent studies, the species and relative populations of gut bacteria determined the likelihood that a cancer patient would respond to drugs known as ‘immune control inhibitors’.
This research has shown that the differences in the gut microbiome between individual patients are related to different outcomes for these drugs. But the exact mechanisms underlying microbiome-immune interactions remain unclear.
Can fecal microbial drugs help treat melanoma?
Oncologists often treat patients with advanced melanoma using immunotherapies that target specific proteins on the surface of immune cells known as PD-1 and CTLA-4. However, it works in a subgroup of patients – 50% -70% of patients have cancer that gets worse despite treatment. No medical treatments have been approved for the treatment of melanoma patients who have failed PD-1 immunotherapies.
To investigate whether certain types of microbes can 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 it to cancer patients who did not benefit do not have. drugs from the checkpoint.
We select feces from patients who respond well to immunotherapy, based on the idea that they will have larger amounts of bacteria to shrink the cancer. Since it is difficult to identify one or two species of bacteria that are responsible for the beneficial response to these treatments, we used the entire bacterial community – hence fecal micro-transplantation.
Transplant recipients were patients whose melanoma never responded to immunotherapy. Both recipients and donors were examined for diseases to ensure that no infectious agents were transmitted during the transplant. After a biopsy of their tumor, patients received a fecal microbial 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 microbial transplant 12 weeks after treatment. Patients whose cancer had shrunk or remained the same size after receiving the fecal microbial transplant for up to two years pembrolizumab.
Results of new clinical trial
After this treatment with fecal micro-transplants, tumors from six out of 15 patients in the study had tumors that shrank or remained the same. The treatment is well tolerated, although some of the patients had minor side effects, including fatigue.
When we analyzed the intestinal microbiota of treated patients, we noticed that the six patients whose cancer had stabilized or improved showed an increase in the number of bacteria previously associated with responses to immunotherapy.
My colleagues and I also analyzed the blood and tumors of respondents. Thus, we observed that the respondents have lower levels of adverse immune cells, called myeloid cells, and higher levels of memory immune cells. Furthermore, by analyzing proteins in the blood serum of treated patients, we observed a decrease in the levels of important immune system molecules associated with resistance in respondents.
These results suggest that the introduction of certain intestinal microorganisms into the patient’s colon can help the patient to respond to drugs that improve the immune system’s ability to recognize and kill tumors.
Ultimately, we hope to go beyond fecal microbial transplants to specific collections of microbes in cancers other than melanoma, thus paving the way for standardized microbial-based drug therapy to treat immunotherapy-resistant tumors.
[The Conversation’s science, health and technology editors pick their favorite stories. Weekly on Wednesdays.]
This article was published from The Conversation, a non-profit news site dedicated to sharing ideas from academic experts. It was written by: Diwakar Davar, University of Pittsburgh.
Read more:
Diwakar Davar receives research funding from Arcus Biosciences, BristolMyersSquibb (BMS), Checkmate Pharmaceuticals, CellSight Technologies, Merck, GlaxoSmithKline (GSK). Diwakar Davar receives compensation for advice from Checkmate Pharmaceuticals, Shionogi, Vedanta Biosciences.