Three therapeutic regulatory approvals in less than a year signal that the promise of the human microbiome may finally be paying off. All of the approved therapies focus on treating recurrent Clostridium difficile infection, but what is next for the field?

With promising oncology-related trial results from a number of researchers and companies such as MaaT Pharma and Enterome, cancer could be the next microbiome frontier to be conquered.

Initially treated as a last resort by doctors for treating people with recurrent C. difficile for whom antibiotics are ineffective, fecal microbiota transplant (FMT) is fast becoming the treatment of choice for this indication. The first randomized controlled trial FMT) for treatment of C. difficile was published in 2013, and interest rapidly grew from there.

In November 2022, Australian regulators approved BiomeBank’s Biomictra donor-derived FMT product, and the FDA approved Rebyota from Ferring Pharmaceuticals, a donor-derived, rectally-administered FMT product, both for treatment of recurrent C. difficile infection. In April of this year, Seres Therapeutics’ oral capsule FMT treatment for the same indication, developed in collaboration with Nestlé Health Science, was also given the green light by the FDA.

It is still a young field, but these approvals show it is possible to get a microbiome product to market. “It was always hanging over our heads that there had never been an approval in the space,” Stephanie Culler, CEO and co-founder of U.S.-based microbiome biotech Persephone Biosciences, told Inside Precision Medicine. “Now that there’s an approval, that means there’s a clear regulatory path… it is a step forward for the entire community.”

The last 12 months have not all been rosy for microbiome researchers and companies, as there have also been a number of notable trial failures, such as those of Finch Therapeutics, Evelo Biosciences, and Kaleido Therapeutics. However, researchers, investors, and companies in this space are now exploring what is next for the microbiome space, and one serious contender is microbiome-based cancer therapeutics.

“Cancer is one of the areas where microbiome therapy has the most potential,” said Isabelle de Cremoux, CEO of VC investment firm Seventure Partners, which focuses on the microbiome space.

Cancer and the gut microbiome

The composition of the gut microbiome is now known to have broad impacts on human health. When balanced and healthy, the gut microbiome can help our bodies to function as they should, but when it becomes disrupted it can also trigger diseases such as cancer.

Some gut bacteria, such as Helicobacter pylori, can be a direct cause of gastric cancer, whereas others cause long-term inflammation that can lead to cancer. Generalized gut dysbiosis, where the microbial ecosystem is disrupted—often by excessive antibiotic use—has also been linked to cancer onset in research studies.

Over the last 20 years, the cancer immunotherapy revolution has changed the face of oncology and cancer treatment. Some cancers are able to protect themselves from the body by stimulating immune checkpoints such as PD-1 that dampen the body’s immune response to cancer. The invention of immune checkpoint inhibitor drugs that can block this defense and help fight cancer led to James Allison and Tasuku Honjo winning the Nobel Prize in Physiology or Medicine in 2018.

The first immune checkpoint inhibitor, ipilimumab (Yervoy), was approved by the FDA in 2011, and there are now eight on the market, including MSD’s blockbuster therapy pembrolizumab (Keytruda).  “In patients who respond, there are fantastic results for these immunotherapies in what were previously very difficult-to-treat cancers. But actually, the proportion of patients responding is still quite low,” commented Tim Sharpington, CEO of the U.K.-based biotech Microbiotica.

Since it first became clear that at least half of the patients given checkpoint inhibitors do not respond, researchers have been trying to understand why. A series of research papers beginning around 2015 have linked the gut microbiome of patients to poor response to checkpoint inhibitors, culminating in two studies carried out in cancer patients that were published in 2021 (Baruch et al. and Davar et al.).

“They took donor stool from patients who responded to anti-PD1 therapy and gave it to non-responding patients. They changed the response phenotype in a proportion of those patients, so patients changed from non-responders to responders, which got everybody really excited, as you can imagine,” explained Sharpington.

“Around 80% of our immune cells are in our gastrointestinal tract. What’s likely happening is that the metabolites that these microbes produce, as well as, potentially, proteins on the outside of them, stimulate the immune system,” said Culler.

Harnessing the power of beneficial bacteria

Microbiotica is one company trying to harness the power of beneficial gut bacteria to help treat cancer patients. Sharpington and colleagues have assembled a large reference library of gut microbes based on earlier work carried out at the Wellcome Sanger Institute near Cambridge.

“There’s been a whole number of studies showing the checkpoint inhibitor response correlation, but they all disagree which bacteria were involved, and that’s because of poor bacterial classification,” said Sharpington. He explained that this is due to most bacterial reference genomes not being detailed enough to identify individual species or strains.

Microbiotica’s chief scientific officer and co-founder, Trevor Lawley, a group leader at the Sanger, and colleagues spent 10 years mass culturing and building a physically assembled reference genome database, which the company has used to identify the bacterial signature involved in response to checkpoint inhibitors.

Following an initial research and validation period in collaboration with researchers in Cambridge and elsewhere, the company plans to start clinical trials later this year in cancer patients who are non-responsive to checkpoint inhibitor therapies.

“We’re quite excited that we think we found the first universal response signature of gut bacteria,” said Sharpington. “We’ve isolated those bacterial products, and it is made up of nine strict anaerobic bacteria, four of them novel, completely unknown outside our company.”

Another company betting on gut bacteria to help cancer patients is French biotech MaaT Pharma. It is taking two approaches, restoring the gut microbiome in sick patients to improve their prognosis and, similar to Microbiotica, restoring the gut microbiome in cancer patients to help them respond to checkpoint inhibitors.

Its most advanced product, MaaT013, is a donor derived, pooled microbiome treatment given as an enema. It is already in Phase III in patients who have graft versus host disease (GVHD) after undergoing hematopoietic stem cell transplantation to treat blood cancer.

Leukemia patients may require a stem cell transplantation, but one out of two recipients will experience GVHD, which is a reaction of the stem cells against the tissues of the recipient. The condition is normally treated with steroids, and in 50% of patients it will cure the GVHD, but others become steroid-resistant. These patients are usually treated with ruxolitinib, a JAK1/JAK2 inhibitor. Patients who do not respond to ruxolitinib (around 45%) are the target group for MaaT013.

“The survival of those patients is 22% at two months. Once you are on that square, that’s [a] one-way ticket,” explained Hervé Affagard, MaaT CEO and co-founder. “We introduce a high-density microbiome into the rectum of the patients with the idea that we will repair the epithelium. By repairing the epithelium, you also restore the immune homeostasis, which will reduce the intensity of the GVHD.”

After positive results in Phase II showing a doubling of survival in the GVHD patient group, MaaT013 recently moved into Phase III for this indication, and is also being tested in Phase II for treatment of metastatic melanoma. MaaT also has a less advanced oral capsule therapy, MaaT033, being tested to improve survival in allogeneic hematopoietic stem cell transplantation patients, and is carrying out preclinical testing on a product designed to improve checkpoint inhibitor response.

A key feature of MaaT’s therapies is pooling of donor samples, which led to an 18-month trial hold by the FDA during the COVID-19 pandemic due to safety concerns. “The pooling is important to increase the richness and diversity of the product, and also it allows for standardization,” noted Affagard. “The FDA had never validated a pooling approach before, so they have been very demanding with us, but we found a solution. They have accepted the mitigations that we have proposed, but it has taken a while.”

MaaT is also co-culturing its products in one reactor, unlike many companies in this space. “We start with a full ecosystem of 250 species and we co-culture them together. We want always to preserve the ecosystem,” Affagard explained, adding that it is also gives the company a technical advantage as it means fewer bioreactors are needed overall.