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Stool Microbiome Sequencing Sheds Light on Immunotherapy Response in Metastatic Kidney Cancer

NEW YORK – Greater microbial diversity, as well as an abundance of specific bacteria species, may influence response to immune checkpoint inhibition in patients with metastatic renal cell carcinoma, according to a prospective observational study published this week in European Urology.

To conduct their study, a group of researchers from institutions including the City of Hope Cancer Center in Los Angeles and the Translational Genomics Research Institute in Phoenix, collected stool samples from a total of 31 patients with advanced renal cell carcinoma prior to treatment with the anti-PD-1 immune checkpoint inhibitor nivolumab (Bristol Myers Squibb's Opdivo) either as a monotherapy or in combination with the anti-CTLA-4 immune checkpoint inhibitor ipilimumab (Bristol Myers Squibb's Yervoy). Additional stool samples were collected longitudinally at one- and three-month timepoints after beginning treatment with the agents.

To assess the stool microbiome in accordance with patients' response to the checkpoint inhibitors, the researchers performed whole-genome shotgun metagenomic sequencing on the samples and analyzed the results alongside patients' tumor shrinkage.

Of the patients enrolled in the study, 58 percent experienced clinical benefit, which the researchers defined as a complete or partial response to the agents or stable disease for at least four months. In comparison to the patients whose cancers progressed on treatment, the clinical benefit group were found to have higher diversity in their stool microbiome. Beyond the microbiome diversity, though, the researchers were able to pinpoint through their metagenomic sequencing a number of specific bacteria species associated with clinical benefit, the most significant of which were Bifidobacterium adolescentis, Barnesiella intestinihominis, Odoribacter splanchnicus, and Bacteroides eggerthii.

Interestingly, among five of the patients who derived clinical benefit from the checkpoint inhibitors, the researchers also highlighted a specific bacterium, Akkermansia muciniphila, which increased relative to baseline abundance as patients received treatment. In patients who did not derive clinical benefit from the treatment, Akkermansia muciniphila decreased in relative abundance.

This finding from the study — the increase in abundance of specific bacteria in the stool of patients who responded to immune checkpoint inhibitors — was what the researchers pointed to as "the novelty of the study design." Past research has highlighted a link between microbiome diversity and response to immune checkpoint inhibitors, but few have tracked changes in specific species' abundance over the course of treatment.

"These results suggest that certain species appear to expand in relative abundance in patients deriving clinical benefit," wrote the authors, who highlighted the fact that their results represented the first US-based study seeking an association between microbiome composition and immunotherapy response in metastatic renal cell carcinoma.

The study did have its limitations — namely, the small number of patients enrolled and the inconsistency in patients' compliance with providing stool samples. To address the former, author Sarah Highlander of the Translational Genomics Research Institute said in a statement that the next steps should be to expand the study into a larger group of patients and track their outcomes over a longer period of time.

Additionally, the results of the study have led to the initiation of a randomized Phase I trial evaluating the role of gut microbial modulation in checkpoint inhibitor response. Specifically, the trial is designed to randomize patients to receive either standard first-line nivolumab and ipilimumab or the combination with the addition of a strain of Clostridium butyricum called CBM588, which is believed to foster the development of a more favorable microbiome that includes the species associated with checkpoint-inhibitor response in this study. The trial's primary endpoint will be the measurement of change in Bifidobacterium in patients' stool samples, while the secondary endpoints — including microbiome diversity, patients' overall response to treatment, and progression-free survival — will provide insight into the potential benefit of modulating the microbiome.