Go with your gut (microbiome)

Study details results on a new method for treating immunotherapy-resistant melanoma patients

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CORVALLIS, Ore.—Two Oregon State University (OSU) researchers looked to the gut micrombiome to craft a way to help immunotherapy-resistant melanoma patients respond to a potential groundbreaking life-saving treatment with long-term benefits. The entire team’s findings from a recent clinical study were published in the Feb. 5 online version of peer-reviewed journal ScienceMag.org, entitled “Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients.”

Without this unique therapy, melanoma patients who do not respond to immunotherapy have “no hope” for treating their melanoma, especially in the advanced stages of skin cancer, says Andriy Morgun, associate professor of pharmaceutical sciences of the OSU College of Pharmacy.

Morgun and colleague Natalia Shulzenko of OSU’s Carlson College of Veterinary Medicine are credited with inventing the statistical modeling technique known as transkingdom network analysis, which is tasked with breaking down and identifying millions of cells in search of the correct formula.

The human gut microbiome is a community of more than 10 trillion microbial cells from about 1,000 different bacterial species, Morgun says. The transkingdom network analysis integrates multiple types of “omics” data—metagenomic, metabolomic, lipidomic, proteomic, etc.—to determine how interactions among specific types of gut microbes help or hinder biological functions in the host.

The microbial interactions indicated how well the body responded to a type of cancer treatment known as anti-programmed cell death protein therapy, abbreviated to anti-PD-1 therapy, Morgun explains. This allows immune cells to react more strongly to cancer.

Morgun remarks that the study results  “were pretty dramatic. We found altering the gut microbiome can take a patient with advanced melanoma, who has never responded to immunotherapy—which fails about 60 percent of the time with this kind of cancer—and converts the patient into one who responds to it.”

As noted in the paper, “Responders exhibited increased abundance of taxa that were previously shown to be associated with response to anti–PD-1, increased CD8+ T cell activation, and decreased frequency of interleukin-8–expressing myeloid cells. Responders had distinct proteomic and metabolomic signatures, and transkingdom network analyses confirmed that the gut microbiome regulated these changes.”

“Natalia and I have been working on the role of gut microbiota in different diseases for more than 10 years, now,” Morgun tells DDN. “Our sequencing technologies and analytical methods allowed us to tell which and how many microbes are in a fecal or tissue sample. This method was used to find which bacteria potentially contributes to beneficial effect of anti-PD1 and which bacteria best improves the treatment outcome.

“The next step includes new trials by our collaborators at Pitt (the University of Pittsburgh) and NCI (National Cancer Institute), and finding which bacteria exactly is causing the beneficial effect. We also want to move from fecal microbiota transplant to ‘bacterial cocktails’ and establish which bacteria might help which patient, for a more personalized treatment. We will also be establishing better approaches to ensure that fecal microbiota transplant is ‘accepted’, and to identify biomarkers to indicate whether a given patient would benefit from FMT.”

Morgun and former OSU postdoctoral researcher Richard Rodrigues, now at the National Cancer Institute (NCI), were part of a collaboration led by immunologists Giorgio Trinchieri and Amiran Dzutsev from NCI and medical oncologists Hassane Zarour and Diwakar Davar of the University of Pittsburgh that tested fecal microbiota transplants’ ability to help melanoma patients benefit from anti-PD-1 immunotherapy.

The scientists collected fecal samples from patients who responded particularly well to the therapy, and in a clinical trial gave the samples, via colonoscopy, to advanced melanoma patients who had never before responded to immunotherapy. The patients then received the anti-PD-1 drug pembrolizumab, and this had the desired effect, turning non-responders into responders.

“Putting everything together, we showed that the fecal microbiota transplants and anti-PD-1 drug can change the gut microbiome and effectively reprogram a tumor’s microenvironment so anti-PD-1 resistance is overcome,” Morgun reports.

According to the study, of 15 patients with advanced melanoma who received the combined treatment, six showed either tumor reduction or disease stabilization that lasted for more than a year.

“The promising findings clearly warrant more investigation in bigger clinical trials,” Morgun points out. “That way we can better identify microbial, bloodstream, and intratumor biomarkers to select melanoma patients most likely to benefit from microbiome-based therapy.”

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