Complex Link Between Gut Microbiome and Immunotherapy Response in Advanced Melanoma

Sharon Worcester

March 07, 2022

A large-scale meta-analysis has verified that the gut microbiome does influence patients' response to immune checkpoint inhibitor (ICI) therapy in advanced melanoma, but the relationship appears to be more complex than previously thought.

Overall, researchers identified a panel of species, including Roseburia spp. and Akkermansia muciniphila, associated with responses to ICI therapy. However, no single species was a "fully consistent biomarker" across the studies, the authors explain.

This "machine learning analysis confirmed the link between the microbiome and overall response rates (ORRs) and progression-free survival (PFS) with ICIs but also revealed limited reproducibility of microbiome-based signatures across cohorts," Karla A. Lee, PhD, a clinical research fellow at King's College London, UK, and colleagues report. The results suggest that "the microbiome is predictive of response in some, but not all, cohorts."

The findings were published online February 28 in Nature Medicine.

Despite recent advances in targeted therapies for melanoma, less than half of the those who receive a single-agent ICI respond and those who receive combination ICI therapy often suffer from severe drug toxicity problems. That is why finding patients more likely to respond to a single-agent ICI has become a priority.

Previous studies have identified the gut microbiome as "a potential biomarker of response as well as a therapeutic target" in melanoma and other malignancies, but "little consensus exists on which microbiome characteristics are associated with treatment responses in the human setting," the authors explain.

To further clarify the microbiome–immunotherapy relationship, the researchers performed metagenomic sequencing of stool samples collected from 165 ICI-naive patients with unresectable stage III or IV cutaneous melanoma from 5 observational cohorts in the Netherlands, United Kingdom, and Spain. These data were integrated with 147 samples from publicly available datasets.

First, the authors highlighted the variability in findings across these observational studies. For instance, they analyzed stool samples from one UK-based observational study of patients with melanoma (PRIMM-UK) and found a small but statistically significant difference in the microbiome composition of immunotherapy responders vs nonresponders (P = .05) but did not find such an association in a parallel study in the Netherlands (PRIMM-NL, P = .61).

The investigators also explored biomarkers of response across different cohorts and found several standouts. In trials using ORR as an endpoint, two uncultivated Roseburia species (CAG:182 and CAG:471) were associated with responses to ICIs. For patients with available PFS data, Phascolarctobacterium succinatutens and Lactobacillus vaginalis were "enriched in responders" across 7 datasets, and significant in 3 of the 8 meta-analysis approaches. A muciniphila and Dorea formicigenerans were also associated with ORR and PFS at 12 months in several meta-analyses.

However, "no single bacterium was a fully consistent biomarker of response across all datasets," the authors wrote.

Still, the findings could have important implications for the more than 50% of patients with advanced melanoma who don't respond to single-agent ICI therapy.

"Our study shows that studying the microbiome is important to improve and personalize immunotherapy treatments for melanoma," study co-author Nicola Segata, PhD, principal investigator in the Laboratory of Computational Metagenomics, University of Trento, Italy, said in a press release. "However, it also suggests that because of the person-to-person variability of the gut microbiome, even larger studies must be carried out to understand the specific gut microbial features that are more likely to lead to a positive response to immunotherapy."

Co-author Tim Spector, PhD, head of the Department of Twin Research & Genetic Epidemiology at King's College London, added that "the ultimate goal is to identify which specific features of the microbiome are directly influencing the clinical benefits of immunotherapy to exploit these features in new personalized approaches to support cancer immunotherapy."

In the meantime, he said, "this study highlights the potential impact of good diet and gut health on chances of survival in patients undergoing immunotherapy."

This study was coordinated by King's College London, CIBIO Department of the University of Trento and European Institute of Oncology in Italy, and the University of Groningen in the Netherlands, and was funded by the Seerave Foundation. Lee, Segata, and Spector have disclosed no relevant financial relationships.

Nature Med. Published online February 28, 2022. Full text

Sharon Worcester is an award-winning medical journalist at MDedge News, part of the Medscape Professional Network.


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