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Integrated Tumor, Microbiome Features Influence Immunotherapy Combo Effects in Advanced Melanoma

NEW YORK – An MD Anderson Cancer Center- and Gustave Roussy Cancer Campus-led team proposed potential tumor and gut microbiome markers of treatment response, or toxicity, in advanced melanoma patients receiving combined anti-PD-1 and anti-CTLA-4 checkpoint blockade treatment.

"There's been a lot of work on genomic markers and immune markers that might predict response and/or toxicity to treatment with combined immune checkpoint blockade, but less focus on the gut microbiota," explained co-senior author Jennifer Wargo, a surgical oncology researcher at MD Anderson, noting that the new study offers a more integrative view of the tumor, immune, and microbial markers associated with response or toxicity following this combined immune checkpoint blockade, or CICB, treatment.

As they reported in Nature Medicine on Thursday, Wargo and her colleagues used exome sequencing, targeted 16S ribosomal RNA sequencing, metagenomic sequencing, immunohistochemistry- or flow cytometry-based immune cell profiling, and/or T-cell receptor sequencing to profile tumor, blood, and/or fecal samples from up to 77 advanced melanoma patients treated with the CTLA-4 targeting drug ipilimumab (Bristol-Myers Squibb's Yervoy) in combination with either nivolumab (Opdivo from Bristol Myers Squibb) or pembrolizumab (Merck's Keytruda).

More than 80 percent of the patients included in the study had stage IV disease, they noted, and nearly half of the patients experienced severe immune-related adverse events classified as grade 3 or higher, ranging from colitis and related weight loss symptoms to infections affecting other organs. Such treatment toxicity appeared to be more common in CICB-treated individuals with higher-than-usual levels of Bacteroides intestinalis and other microbial representatives in their gut, based on 16S sequence profiles in fecal samples from 54 patients.

Follow-up experiments in mouse models of colitis-related toxicity suggested this gut microbial shift coincides with a rise in mucosal interleukin-1-beta levels, but might be mitigated using fecal microbiota transfer, or FMT, providing a mechanistic look at the microbiome-treatment response relationship and potential strategies for avoiding toxicities and boosting checkpoint blockade immunotherapy responses with new or existing drug targets or treatments.

"We are beginning to move beyond associations and really starting to see causal effects and mechanisms," explained co-author Michael White, with MD Anderson's surgical oncology department. "As soon as you begin to delve into mechanisms and really define those, you can begin to hypothesize about actionable targets."

Along with toxicity-related gut microbiome features, the researchers highlighted several tumor and immune features that appeared to correspond to CICB treatment response, including some of the same markers that have been proposed for checkpoint blockade monotherapies in the past.

Based on exome sequence data for 26 of the pre-treatment melanoma tumors, for example, they found that tumor mutational burden was higher in the 20 CICB treatment responders than in the six advanced melanoma patients who did not respond to the combined immunotherapy. Treatment response also appeared to be enhanced in those with increased immune CD8+ T-cell density in their tumors, while non-response corresponded to more copious copy number losses, particularly involving sequences on chromosome 5, chromosome 10, or chromosome 15.

While gut microbial diversity was similar in CICB treatment responders and non-responders, the team pointed to a few specific taxa with altered representation in the guts of those who did or did not seem to benefit from the checkpoint blockade combination. In particular, Bacteroides stercoris and Parabacteroides distasonis were among the species enriched in the guts of treatment responders — results they confirmed with metagenomic sequencing on samples from 27 treatment responders and 11 non-responders.

These and other findings point to the possibility of developing strategies such as phage therapy, targeted treatment, dietary interventions, or FMT to boost treatment response and stave off troublesome toxicities, while providing avenues for biomarker development that go beyond tumor or immune features.

"As we get more of an understanding, we need to build models of integrated biomarkers," Wargo said. "Certainly, there are people who are working on that using medical modeling and other approaches, which is fantastic. That's exactly where we need to go."