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A new study by researchers at the Wellcome Sanger Institute, the Olivia Newton-John Cancer Research Institute in Australia and collaborators has identified specific strains of bacteria that are linked to a positive response to combination immunotherapy in the largest study of its kind. .
The study is published in Nature medicine In an article titled “A Gut Microbial Signature for Combined Immune Checkpoint Blockade in All Cancer Types”, and details a distinctive collection of microorganisms in an individual’s gut bacteria that may help identify those that would benefit from combination immunotherapy and help explain why the effectiveness of this treatment is difficult to predict.
“Immune checkpoint blockade (ICB) targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte protein 4 (CTLA-4) can induce remarkable, although unpredictable, responses in a variety of cancers,” the researchers wrote. “Studies suggest that there is a relationship between the composition of the intestinal microbiota of a cancer patient and the clinical response to BCI; however, defining microbiome-based biomarkers that generalize across cohorts has been challenging.”
Although immunotherapy can be very effective, it only works on a proportion of recipients in a wide range of cancers. Being able to predict who is most likely to respond to treatment helps ensure that patients do not suffer these unnecessary side effects without medical benefit.
The study used samples collected in a large Australian multicenter clinical trial where combination immunotherapy was effective in 25% of people with a wide range of rare advanced cancers, including rare gynecological cancers, neuroendocrine neoplasms, and upper gastrointestinal and biliary cancers. .
The clinical trial focused on checkpoint inhibitors. These anticancer agents block the body’s immune checkpoint proteins, allowing immune cells to destroy cancer cells. In this case, immunotherapy blocked the PD-1 and CTLA-4 checkpoints.
The researchers used stool samples from patients from clinical trials and performed deep metagenomic sequencing to map all the organisms within the participants’ microbiomes, down to the strain level.
They discovered multiple strains of bacteria in those who responded well to the treatment, many of which had not been cultured before. This allowed them to identify a microbiome signature that was found in patients who responded well to treatment.
The researchers conducted a meta-analysis of previous studies and found that their signature can be applied to different cancers, such as melanoma, and across countries, to predict individuals whose cancer is likely to respond to combination immunotherapy.
However, when applied to patients who received only one of the immunotherapy drugs, targeting only the immune checkpoint receptor PD-1, the machine learning model was unable to identify those who would respond to the treatment.
This suggests that the relationship between gut microbiota and treatment response is specific to particular therapeutic combinations.
Ashray Gunjur, PhD, first author from the Wellcome Sanger Institute and the Olivia Newton-John Cancer Research Institute, Australia, said: “Our study shows that understanding the microbiome at the strain level, not just the species level, can open up a new road”. level of personalized medicine. Having that extra resolution is crucial if we want to understand what is happening in the human body and the interaction between cancer treatment and the microbiome. “Being able to test the specific mechanisms of this relationship between specific strains and response is the next horizon of this research, and could benefit human health in many ways.”