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Microbiome

Inspired by the microbiome, can poop pills and gut bugs help boost cancer immunotherapy’s effects?

Companies are testing the ability of fecal transplants and bacteria-stuffed pills to make checkpoint inhibitors work for more people

by Ryan Cross
April 17, 2019 | APPEARED IN VOLUME 97, ISSUE 16

 

09716-feature2-seres.jpg
Credit: Seres Therapeutics
A scientist working with anaerobic bacteria at Seres Therapeutics

When launching her new microbiome-based cancer drug start-up, Stephanie Culler ran into an unexpected problem: she couldn’t find enough poop.

Poop is the currency of companies like the one she cofounded, Persephone Biome, which study the trillions of microorganisms that make up our gut microbiomes. The companies are all building on recent discoveries that suggested that certain bacteria living in our gut—and expelled in our stool—could alter the effectiveness of cancer therapies.

Culler had followed the work emerging from academic labs and companies that used fecal microbiota transplants to transfer poop—and thus microbes—from healthy people into people whose tumors stubbornly wouldn’t shrink despite treatment. It was a crude concept.

“Frankly, I was disappointed by the lack of rigor and quantitative tools,” says Culler, who 2 years ago left her job as a microbe engineer at the industrial biotech company Genomatica to cofound Persephone Biome. She proposed a data-driven alternative to fecal transplants that would require profiling the bacteria found in the poop of healthy people, people with cancer, and people in remission. The goal was to pinpoint bugs that were missing from people who didn’t respond to cancer treatment and make pills to replace them.

But first she needed stool samples. They were surprisingly hard to come by.

“There is a lot of stigma for giving stool,” she says. In the company’s first attempts to recruit donors, Culler found that people would rather be poked with needles than donate poop. Part of the problem was the embarrassment factor, coupled with the awkward, tricky-to-use collection containers. So Culler’s company designed a simpler poop collection kit, wrapped it in a package resembling a luxury handbag, and put a fun spin on recruiting donors through a campaign called Poop for the Cure, which involved Culler’s cofounder dressing up in a poop emoji costume at cancer fundraisers. “That poop emoji is extremely popular,” she says.

In just a year and a half, Persephone, based in Johnson & Johnson’s start-up incubator JLabs in San Diego, has amassed about 1,400 donors and identified just under a dozen microbes missing from people who didn’t respond to cancer treatments.

Culler’s company isn’t the only one attempting to probe and prod our inner denizens to demystify the microbiome’s role in cancer. At least a dozen companies have programs that use microbes or microbe-inspired approaches to increase the efficacy of existing cancer drugs. Specifically, many plan to test their therapies alongside checkpoint inhibitors, widely used drugs that unleash our immune cells on tumors by blocking proteins called CTLA4 or PD-1. Checkpoint inhibitors—seven of which are approved—work great for some, but not most, people with cancer, and companies are scrambling to find the missing variables that explain why. The microbiome might be one of them.

The first big clue connecting the microbiome and cancer drug efficacy came in 2013, when two groups showed that some traditional immunotherapy and chemotherapy drugs didn’t work well in mice without microbiomes or mice whose microbiomes had been blasted with antibiotics. The potent effects of some chemotherapies seem to depend partly on gut bacteria slipping through damaged intestinal walls and kicking neighboring immune cells into high alert.

The implications took some time to sink in, even for microbiome companies like Vedanta Biosciences that were already designing therapies to restore good bugs in the gut for conditions like inflammatory bowel disease. “I was not sure I believed it,” recalls Bernat Olle, CEO of Vedanta.

Then in 2015, two groups showed that specific species of gut bacteria were needed in mice for checkpoint inhibitors to work. “You could argue about which microbes were responsible for that, but it was pretty clear that if you took the microbiota away, the effect of anti-CTLA4 was gone,” Olle says. When human poop was transplanted into the mice, the drugs started working (Science 2015, DOI: 10.1126/science.aad1329). “That paper opened our eyes,” he adds. A detailed mechanism explaining how fecal transplantation works is lacking, but experts agree it must be related to the simple fact that the majority of our immune cells live in close contact with our guts.

Vedanta and other microbiome companies began adding cancer programs to their pipelines, but the watershed moment arrived in late 2017 when three academic groups published three papers identifying distinct microbiome signatures for people who did and didn’t respond to PD-1 checkpoint inhibitors. “At first, we literally thought we were wrong,” recalls Christine Spencer, who was the graduate student that analyzed data in the study led by Jennifer Wargo at MD Anderson Cancer Center (Science 2017, DOI: 10.1126/science.aan4236). “We tried every single thing to make sure this was a true result, because these effects were quite strong.”

Those studiesboth solidified and complicated the field: people who responded to the checkpoint inhibitors harbored certain types of bacteria that were missing in the nonresponders, but each academic group pointed to different species as the culprits. “We really don’t know which bugs are good and not good yet,” says Giorgio Trinchieri, who led one of the 2013 antibiotic studies at the National Cancer Institute.

Cancer drugs inspired by bugs

Many companies are testing or plan to test their microbiome therapies in combination with an anti-PD-1 checkpoint inhibitor such as Merck & Co.’s Keytruda or Bristol-My- ers Squibb’s Opdivo.

Sources: Sponsors.

A way around that could be to simply transplant stool from people with cancer who get better after checkpoint inhibitor therapy into the guts of those who are not responding to the drugs. Trinchieri, along with colleagues from the University of Pittsburgh and collaborators at Merck & Co., presented data from the first of two fecal microbiota transplant studiesin people with cancer at the American Association for Cancer Research meeting in April. The trial was tiny, just three people. One person’s tumor shrank after transplant, and another person’s tumor stopped growing. A third person didn’t benefit from the treatment. A separate group in Israel reported similar results. “It is promising and doesn’t seem to be harmful for the patients, but we need to do more,” Trinchieri says. A larger Phase II study of about 20 people is underway in Pittsburgh.

Lest poop transplants sound unsavory, several biotech companies have already been developing therapies that remove, or at least minimize, any stool transfer. One of those is Seres Therapeutics, which relies on stool samples from healthy donors to make poop pills—oral drugs containing the spores of bacteria that Seres has identified as being important for inducing a checkpoint response. The company has teamed up with MD Anderson and the Parker Institute for Cancer Immunotherapy to test those pills with checkpoint inhibitors.

Others, such as Vedanta and Persephone, are packing pills with strains of bacteria that they’ve cultured in the lab but were originally isolated from human stools. “This is a deliberate effort to take several steps beyond the black box that is fecal transplantation,” Olle says. In January, Vedanta’s scientific cofounder Kenya Honda published a study detailing 11 rare bacterial strains found in healthy human guts that activate immune cells called killer T cells to attack Listeria infections and tumors when given to mice (Nature 2019, DOI: 10.1038/s41586-019-0878-z). Vedanta plans to begin testing its pill with Bristol-Myers Squibb’s checkpoint inhibitor in humans this year.

These approaches all come with their own challenges. It will be difficult to pin down why a given fecal microbiota transplant works for one person and not another. Seres depends on donor-provided stools, and it acknowledges that there will be some variability from pill to pill. And Vedanta faces the challenge of fermenting 11 strains of bacteria—some of which have never been manufactured before.

Some companies, such as Evelo Biosciences, are avoiding this complexity by testing the ability of a single microbe to engage immune cells in the small intestine to improve the efficacy of Merck & Co.’s checkpoint inhibitor, Keytruda. 4D Pharma is running a similar trial and in January showed in human cells that its single microbe’s flagellin—the protein that composes a bacterium’s whirling tail—is responsible for igniting the innate immune system (Sci. Rep. 2019, DOI: 10.1038/s41598-018-36926-8).

It could be some time before clinical data indicate whether any of these approaches is successful. In the end, microbiome-based therapies may be just one of many ways to achieve the same goal: boost the efficacy of cancer immunotherapies. “I think the microbiome will be an important play, but I don’t know if it will be the most important,” Trinchieri says.

In the meantime, all the microbiome hype has some scientists worried that people could be turning toward off-the-shelf microbes known as probiotics for help. “There is a perception that taking probiotics is healthy,” says Spencer, who is now a researcher at the Parker Institute. But at the AACR meeting this month, she presented unpublished work from Wargo’s group showing that may not always be the case. Following up on their 2017 study, Spencer found that people with melanoma taking probiotics had decreased gut diversity and were 70% less likely to respond to checkpoint inhibitor therapy than people with melanoma not taking probiotics.

The microbiome companies point out that their therapies are based on bacteria unrelated to the Lactobacillus species widely found in probiotics. “I think the key is to not think of probiotics as a monolithic class,” Olle says. “It really matters which organisms you pick, and that is the whole thesis behind Vedanta.”

Wargo’s group at MD Anderson is now planning a more detailed study to collect information on the kinds of probiotics that patients are using.

In the microbiome, nothing is straightforward, at least for now. But researchers like Culler, who at 13 lost both grandmothers to cancer, have made it their mission to sort it out. Persephone has raised a small amount of seed funding, and Culler is working on raising the start-up’s first major round. She hopes to begin testing her microbe-based therapy in people by the end of next year. She is already facing the difficult reality of watching some of her company’s stool donors die. That fuels her sense of urgency. “I’ve asked myself, ‘Did my grandmothers not have these microbes?’  ” she says. “I made a promise to them to do something about cancer.”

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Comments
ROBERT BLACKLEDGE (April 17, 2019 9:10 PM)
‘Gut feelings’ – an updated version of the ‘Twinkie Defense’?
From C&EN, April 8, 2019, page 37: “Studies have shown that our microbiome may play a role in mental health and neurological conditions such as autism, epilepsy, and depression by interacting with our nervous system and even releasing molecules that can perhaps make their way to the brain.”
Criminal suspect: “My microbiome made me do it.”
Robert Blackledge
ACS ID: rblackle
Member No. 00112191

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