The microbiome can identify those who benefit from combination immunotherapy in many different cancers, including rare gynecological cancers, biliary tract cancers and melanoma.
Researchers from the Wellcome Sanger Institute, the Olivia Newton-John Cancer Research Institute in Australia, and colleagues have identified specific strains of bacteria associated with a positive response to combination immunotherapy in the largest study of its kind.
The study, published today (March 1) in Nature Medicinedetails a collection of microbial signatures in a person’s gut bacteria that may help identify those who would benefit from combination immunotherapy and explain why the effectiveness of this treatment is otherwise difficult to predict.
In the future, understanding more about these strains of bacteria may help develop next-generation probiotics, known as “living biotherapeutics,” that focus on modulating the microbiome to support combination immunotherapy from within.
Immunotherapy is a type of treatment that harnesses the body’s immune system to target cancer. While it can be very effective, it only works in an acceptable percentage of a wide range of cancers. As with all cancer treatments, immunotherapy can have multiple side effects. Therefore, being able to predict who is more likely to respond to treatment helps ensure that patients do not endure these unnecessary side effects without medical benefit.
This study used samples collected in a large, multi-centre Australian clinical trial where combination immunotherapy was effective in 25 per cent of people with a wide range of advanced rare cancers, including rare gynecological cancers, neuro-endocrine neoplasms and upper gastrointestinal and biliary cancers. .
The clinical trial focused on a type of combination immunotherapy known as immune checkpoint inhibitors. These anticancer agents block the body’s immune checkpoint proteins, allowing immune cells to destroy cancer cells. In this case, the immunotherapy blocked the PD-1 and CTLA-4 checkpoints.
Researchers used stool samples from clinical trial patients and performed deep shotgun gene sequencing1 to map all the organisms in participants’ microbiomes, down to the strain level.
They discovered multiple strains of bacteria in those who responded well to treatment, many of which had not been cultured before. This allowed them to identify a microbiome signature found in patients who responded well to treatment.
In addition, the team used this signature to train a machine learning model that could predict who would benefit from combination immunotherapy.
They conducted a meta-analysis of previous studies and found that their signature can be applied to different cancers, such as melanoma, and in different countries, to predict people 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 could not identify those who would respond to the treatment.
This suggests that the relationship between gut microbiota and treatment response is specific to specific treatment combinations. Therefore, the researchers suggest that future development of gut microbiome-based diagnostic tests or therapeutics should be tailored to the immunotherapeutic regimen, regardless of cancer type.
This step toward personalized medicine can help expand cancer treatments to more people and can match people with treatments that will benefit them most.
Dr Ashray Gunjur, first author from the Wellcome Sanger Institute and 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 level of personalized medicine. Having this extra analysis is crucial if we want to understand what happens in the human body and the interaction between cancer treatment and the microbiome. The next thing is to be able to test the specific mechanisms of this relationship between specific strains and response defined in this research, and that could benefit human health in many ways.”
Rare cancers can be difficult to study and treat, and while immunotherapy can be incredibly effective in some of these cases, it can also be unpredictable. Our research shows that the microbiome influences how well someone responds to combination immunotherapy, but that monotherapy works differently. This suggests that the microbiome should be considered when developing future therapeutics. In addition, there is the potential to develop live biotherapeutics that could provide the bacteria that appear to support immunotherapy, helping the microbiome work with the patient to give them the best chance of a response.”
Dr David Adams, co-senior author from the Wellcome Sanger Institute
Dr Trevor Lawley, co-senior author from the Wellcome Sanger Institute, said: “Our microbiomes differ from person to person, as we all have a different ecosystem of bacteria and other organisms that shape our responses to the world around us. Our research highlights how a person’s microbiome can predict how they will respond to cancer treatment, which can have immediate clinical impact by identifying those who will benefit most and help design future clinical trials.”
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Journal Reference:
Gunjur, A., et al. (2024). A gut microbial signature for combinatorial blockade of immune checkpoints in all cancer types. Nature Medicine. doi.org/10.1038/s41591-024-02823-z.
