New microbiome discovery may enhance immunotherapy for various rare cancers

The study, published on 1st March 2024 in Nature Medicine, detailed a collection of microorganisms in an individual’s gut bacteria that may help identify those who would benefit from combination immunotherapy and help explain why the efficacy of this treatment is otherwise hard to predict.

Immunotherapy is a type of treatment that harnesses the body’s immune system to target the cancer. While it can be very effective, it only works in a proportion of recipients across a wide range of cancers. As with all cancer treatments, immunotherapy can have multiple side effects. Therefore, being able to predict who is most likely to respond to treatment helps ensure that patients do not endure these unnecessary side effects for no medical benefits.

In a large clinical trial targeting various advanced rare cancers, including gynaecological, neuro-endocrine, and upper gastrointestinal cancers, researchers utilized stool samples collected from patients. Employing deep shotgun metagenomic sequencing, they mapped the microbiomes of participants at the strain-level. The trial centered on immune checkpoint inhibitors, blocking PD-1 and CTLA-4 checkpoints to empower the immune system to combat cancer cells effectively. Additionally, the team used a machine learning model that could predict who would benefit from combination immunotherapy.

The findings showed multiple strains of bacteria in those who responded well to treatment, many of which had not been cultivated before. This allowed them to identify a microbiome signature that was found in patients who responded well to treatment. However, when applied to patients who received just one of the immunotherapy drugs, targeting the immune checkpoint receptor PD-1 only, the machine-learning model could not identify those who would respond to treatment.

The results suggested that the relationship between gut microbiota and treatment response is specific for particular therapeutic combinations. Therefore, the researchers suggest that future development of diagnostics tests or therapeutics that rely on the gut microbiome should be tailored to the immunotherapy regimen, regardless of cancer type.

“Rare cancers can be hard to study and treat and while immunotherapy treatment can be incredibly effective in some of these cases, it can also be unpredictable. Our research shows that the microbiome impacts how well someone responds to combination immunotherapy, but that monotherapy gives a different result. This suggests that the microbiome should be taken into account when developing therapeutics going forward. In addition to this, there is a possibility of developing live biotherapeutic products that could provide the bacteria shown to support immunotherapy, helping the microbiome work with the patient to give them the best odds of response possible.” said Dr David Adams, co-senior author from the Wellcome Sanger Institute.

Reference: A. Gunjur, Y. Shao, T. Rozday, et al. (2024) A gut microbial signature for combination immune checkpoint blockade across cancer types. Journal: Nature Medicine. DOI: 10.1038/s41591-024-02823-z