The microbiome could be the key to identifying individuals who can benefit from combination immunotherapy across various cancers, including rare gynaecological and biliary tract cancers, as well as melanoma.
Researchers from the Wellcome Sanger Institute, along with the Olivia Newton-John Cancer Research Institute in Australia and collaborators, have pinpointed specific strains of bacteria associated with a positive response to combination immunotherapy in the largest study of its kind.
Published on March 1 in Nature Medicine, the study outlines a unique collection of microorganisms within a person’s gut bacteria that might help pinpoint those likely to benefit from combination immunotherapy. This could shed light on why the effectiveness of such treatment is often difficult to predict.
Delving deeper into these bacterial strains could fuel the development of next-generation probiotics, referred to as ‘live biotherapeutic products’, which could target the microbiome to support combination immunotherapy internally.
Immunotherapy, which mobilises the body’s immune system to combat cancer, can be highly effective but only in a subset of patients across a range of cancers. Like all cancer treatments, immunotherapy can come with various side effects. Therefore, being able to anticipate who will respond best to treatment is crucial to sparing patients unnecessary side effects without any therapeutic benefits.
Dr. Ashray Gunjur, the study’s first author from the Wellcome Sanger Institute and the Olivia Newton-John Cancer Research Institute, told the Oncology Network: “This work is the result of a fantastic collaboration, and shows the potential of well-designed investigator-initiated clinical trials in conjunction with high-throughput genomic research facilities. We hope that gut microbiome profiling will lead to better tailored cancer treatments, to realise the dream of truly personalised cancer care.”
This study drew upon samples collected in a large, multi-centre Australian decentralized clinical trial where combination immunotherapy proved effective in 25 percent of patients with advanced rare cancers, including rare gynaecological cancers, neuro-endocrine neoplasms, and upper gastrointestinal and biliary cancers.
This was a teletrial/decentralized trial run across a network that included regional sites, reflecting that if we can provide better access to trials , we increase the pool of patients able to participate and we can answer important scientific questions more rapidly, Craig Underhill
Professor Craig Underhill, one of the paper’s authors from Border Medical Oncology in Albury-Wodonga, said to the Oncology Network, “This paper has important learnings: we now know gut microbiome profile may influence response to checkpoint inhibitors. This study in patients with rare cancers was a teletrial/decentralized trial run across a network that included regional sites, reflecting that if we can provide better access to trials , we increase the pool of patients able to participate and we can answer important scientific questions more rapidly”.
The clinical trial focused on a form of combination immunotherapy known as immune checkpoint inhibitors, which work by blocking the body’s immune checkpoint proteins, enabling immune cells to attack cancer cells. In this instance, the immunotherapy targeted the PD-1 and CTLA-4 checkpoints.
Researchers analysed stool samples from trial participants using deep shotgun metagenomic sequencing, mapping all organisms within their microbiomes down to the strain level.
They identified multiple bacterial strains in patients who responded well to treatment, many of which had not been previously cultured. This led them to identify a distinct microbiome signature present in patients who responded positively to treatment.
Furthermore, the team employed this signature to train a machine-learning model capable of predicting who would benefit from combination immunotherapy.
A meta-analysis of prior studies revealed that their signature could be applied to different cancers, such as melanoma, and across different regions to predict individuals likely to respond to combination immunotherapy.
However, when applied to patients receiving only one of the immunotherapy drugs targeting the PD-1 immune checkpoint receptor, the machine learning model failed to identify responders.
This indicates that the relationship between gut microbiota and treatment response is specific to particular therapeutic combinations. Hence, the researchers propose that future diagnostic tests or therapeutics relying on the gut microbiome should be tailored to the specific immunotherapy regimen, irrespective of cancer type.
This move towards personalised medicine could expand cancer treatment accessibility and match individuals with therapies offering the greatest benefit.
Further Information: Look out for The OJC Meets Ashray Gunjur coming soon! It will feature an interview with first author Dr Ashray Gunjur, by Professor Craig Underhill, also an author of the paper.
Paper: A. Gunjur, Y. Shao, T. Rozday, et al. (2024) A gut microbial signature for combination immune checkpoint blockade across cancer types. Nature Medicine. DOI: 10.1038/s41591-024-02823-z
With thanks to the Wellcome Sanger Trust
