Melanoma patients respond to immunotherapy after changes to gut microbiome

CORVALLIS, Ore. – Statistical modeling developed by Oregon State University researchers has confirmed that changes to melanoma patients’ gut microbiome led them to respond to a type of treatment capable of providing long-term benefit.

Findings were published in Science.

The modeling technique invented by Andrey Morgun of the OSU College of Pharmacy and Natalia Shulzenko of Oregon State’s Carlson College of Veterinary Medicine is known as transkingdom network analysis.

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

In this case, the microbial interactions involved how well the body responds to a type of cancer treatment known as anti-programmed cell death protein therapy, abbreviated to anti-PD-1 therapy. It allows immune cells to react more strongly to cancer.

“It was pretty dramatic,” said Morgan, associate professor of pharmaceutical sciences. “We found altering the gut microbiome can take a patient with advanced melanoma who has never responded to immunotherapy, which fails about 60% of the time with this kind of cancer, and convert the patient into one who responds to it.”

Morgun and former OSU postdoctoral researcher Richard Rodrigues, now at the National Cancer Institute, 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 time it had the desired effect, turning non-responders into responders. Transkingdom network analyses confirmed the microbiome’s role.

“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 said.

Of 15 patients with advanced melanoma – an aggressive form of skin cancer – who received the combined treatment, six of them 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 said. “That way we can better identify microbial, bloodstream and intratumor biomarkers to select melanoma patients most likely to benefit from microbiome-based therapy. We really expect that eventually we’ll identify a collection of bacteria with a high success percentage for converting immunotherapy non-responders into responders.”

Merck and the National Institute of Health supported this research.

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