Could microbiome drugs be the key to unlocking checkpoint inhibitors’ potential? 

Indeed, the trillions of microorganisms residing in our bodies, particularly in the gut have been shown to influence various aspects of human health, including the immune system. U.K-based company Microbiotica is making yet another statement that microbiome modulation could be the key to unlocking ICIs’ potential.

Indeed, Microbiotica announced today that the European Union (E.U.) and the U.K. granted regulatory approval to proceed to phase 1b studies for two of its microbiome medicines. MB310 will be evaluated for treating ulcerative colitis and the candidate that interests us the most today, MB097 will be evaluated in combination with Merck’s ICI Keytruda against advanced melanoma.

What part does the microbiome play in oncology and do microbiome drugs have the potential to become a standard-of-care treatment in this field? In this article, we take a closer look into microbiome modulation and ICIs’ efficacy.

How does the microbiome enhance ICIs’ efficacy?

Tim Sharpington, chief executive officer (CEO) at Microbiotica stated that there is a growing body of evidence that the microbiome has an impact on our health. “The ecosystem of microbes which has evolved with us over millions of years can cause or ameliorate disease and affect treatment response. The gut microbiome in particular can impact our immune system, and our metabolic system, and there is an increasing appreciation of the importance of the gut-brain axis.”

Research has also been focused on more precise benefits of microbiome modulation. “In terms of immune-oncology, numerous published studies, from 2015 onwards, have demonstrated that a patient’s microbiome can impact their ability to respond to immune checkpoint inhibitors. In 2021, two studies were published which reported that after fecal microbiota transplant (FMT) from melanoma patients who responded to ICI treatment was given to non-responding patients, a proportion of previously non-responding patients then became responsive to re-challenge with ICIs. It is thought that the gut microbiome can modulate the immune system to allow response to ICIs,” said Sharpington.

Indeed, a pivotal moment came in 2021 when two key studies were published, demonstrating the potential of FMT in modulating ICI responses. These studies showed that melanoma patients who did not initially respond to ICIs could be “reprogrammed” by receiving FMT from ICI responders.

The Davar and colleagues study focused on 15 patients with advanced melanoma who had previously shown no response to anti-PD-1 therapy, a common ICI. These patients received FMT from donors who had experienced exceptional responses to the same therapy. Following the transplantation, the patients were re-treated with pembrolizumab, an anti-PD-1 drug. 6 out of the 15 patients (40%) exhibited clinical responses after undergoing the combined FMT and anti-PD-1 therapy.

The study also observed changes in the gut microbiome of these responders, including increased microbial diversity and a shift in the composition of gut bacteria. These changes were associated with enhanced activation of CD8+ T cells, which are crucial for the immune system’s ability to attack and destroy cancer cells.

The Baruch and colleagues study examined ten patients with metastatic melanoma who were also refractory to anti-PD-1 therapy. The study followed the same process as the Davar and colleagues’ study. Comparable results were observed as 3 out of the 10 patients (30%) achieved an objective clinical response, either a reduction in tumor size or stabilization of disease progression.

Similarly, responders displayed favorable changes in their gut microbiota, which were associated with increased immune cell infiltration into tumors and a reduction in systemic inflammation. The study identified specific bacterial species, such as Bacteroides ovatus, that were linked to these positive outcomes.

Microbiotica’s solution takes a side step away from FMT to aim for a more tailored approach.

Microbiotica’s approach: MB097 and the MELODY-1 study

The development of MB097 is grounded in Microbiotica’s platform, which combines bioinformatics with an extensive microbiome genome database. “We have built a platform, based on many years of work at the Wellcome Sanger Institute, which allows us to analyze large clinical datasets and precisely identify specific microbiome signatures associated with phenotype and drug response in specific patient populations. This provides the basis for our precision microbiome therapeutic development programs,” explained the biotech’s CEO.

The process began with the analysis of the microbiomes of melanoma patients across multiple independent clinical trials. “We analyzed the microbiome of melanoma patients in four independent clinical trials and, utilizing our microbiome platform, identified a small group of bacteria that significantly raised in abundance in patients who responded to ICI therapy. This was the basis of the strain selection for our manufactured live biotherapeutic product (LBP) MB097,” said Sharpington.

MB097 is composed of a defined consortium of nine specific bacterial strains, including four novel species that had not been previously characterized. The strains were selected based on their ability to promote key immune responses, including the activation of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, which are crucial for tumor destruction.

This consortium might be where Microbiotica’s approach has an edge over traditional FMT. “FMT, by its nature, is dependent on donors and can therefore be varied in content,” said Sharpington. According to him, the challenge lies in the identification and selection of which bacteria to use, but it is also the key to a more predictable and stable outcome.

Another advantage Microbiotica’s CEO puts forward is the scalability of the solution. “Once we identified our consortia of bacteria, we needed to develop and scale up manufacturing processes for each strain. Now that this is in place, we can manufacture our product in a controlled, consistent, and scalable way, which is a clear advantage over donor-derived FMT products.”

Now that preclinical studies have demonstrated strong results, Sharpington is eagerly looking toward the MELODY-1 trials. “Our preclinical studies showed that MB097 stimulates core pathways of the immune system to activate CTLs, and NK cells.”

“In our MELODY-1 trial, we will be recruiting patients who have not responded to prior treatment with an anti-PD1 inhibitor, such as Keytruda. We will be measuring standard oncology endpoints including imaging measurements of tumor response, measuring the engraftment of the strains we are dosing, several immune biomarkers, and of course, the safety and tolerability of the combination therapy,” said Sharpington.

Who else is in the microbiome modulation space beyond Microbiotica?

Microbiome modulation to improve ICIs’ activity is indeed a promising approach, and Microbiotica is not alone in the area. Several companies are making strides and if they keep the progress going, the future of the field might be even brighter. Here are some names to keep an eye on in addition to Microbiotica.

Maat Pharma

MaaT Pharma, based in France, is developing microbiome therapies primarily aimed at hematological and immuno-oncology applications. They focus on restoring immune homeostasis to improve patient responses to cancer treatments.

MaaT013 is one of the company’s lead candidates in a phase 3 trial targeting graft-versus-host disease (GvHD), while MaaT034 is being explored as an adjunct to ICIs in melanoma patients.

Seres Therapeutics

Seres Therapeutics is a well-known player in the microbiome therapeutics space, especially for its work on recurrent clostridium difficile infection (rCDI), a bacterial infection that primarily affects the large intestine. The company is also exploring the microbiome’s role in immune modulation and is expanding into immuno-oncology.

Its lead product, Vowst, was recently approved by the U.S. Food and Drug Administration (FDA) for rCDI. It is also developing SER-401, a microbiome therapeutic intended to enhance the efficacy of ICIs in cancer treatment, currently in phase 1 trials​.

Microba

Australian company, Microba, focuses on using high-precision metagenomic analysis to develop microbiome-based therapies. Its technology allows for detailed mapping of the gut microbiome, identifying key bacterial species that could influence immune responses.

Microba is advancing a pipeline of live biotherapeutic candidates, including a program designed to work in conjunction with ICIs to enhance anti-tumor immunity. The company’s focus is similar to Microbiotica’s and its pipeline is still mostly preclinical.

Genome & Company

Genome & Company, headquartered in South Korea, is focusing on combining microbiome modulators with established cancer immunotherapies to enhance their effectiveness.

The company is conducting phase 2 trials in collaboration with Pfizer and Merck, aiming to improve the performance of ICIs like pembrolizumab against solid tumors by integrating specific gut microbes into treatment regimens​.

What’s next for Microbiotica and microbiome modulation in oncology and beyond?

In several years, the market for microbiome therapeutics could be packed, and not only with solutions to improve ICIs activity in oncology. As the understanding of the intricate relations between the microbiome and health conditions and its potential to enhance existing treatments increases, the indications of microbiome therapeutics will multiply.

According to Microbiotica’s CEO, there is still a long way to go  but there are numerous possibilities.

“The development of microbiome therapeutics is still a relatively new modality and a number of different approaches are being investigated, from full FMT to single strain LBPs and phage therapy aimed at removing pathogenic gut bacteria, in a number of different therapeutic indications.” Tim Sharpington, chief executive officer (CEO) at Microbiotica

This is why Sharpington highlights the importance of demonstrating safety and signs of efficacy as a company but also as part of gaining additional knowledge about how best to design and target LBPs.

As Sharpington puts it, “The first microbiome therapeutics, FMT-based treatments for gastrointestinal infection have now been approved. We anticipate that the next developments will be in more specifically targeted therapeutics which exploit the microbiome’s role in immune modulation.”

As for Microbiotica’s candidate in particular, Sharpington is confident about its integration into oncology practices, as it continues to be successful in trial settings. “We believe that MB097 certainly has the potential to be used as a first-line adjunct therapy. One of the advantages of LBPs based on commensal bacteria is their benign safety profile. If this is repeated with MB097, we have the potential to enhance the efficacy of ICIs without additional toxicities.” While this is true for MB097, it also applies to other similar solutions.

Gut microbiome modulation could also have potential beyond melanoma indicated Sharpington. “Over recent years there have been additional studies published showing a link between the gut microbiome and response to ICIs in a number of different cancers, including non-small cell lung cancer (NSCLC) and renal cell carcinoma. The MITRE study is evaluating the microbiome as a biomarker of efficacy and toxicity in cancer patients receiving ICI therapy in twelve U.K. study centers and will provide further evidence in different tumor types.”

Reflecting on the company’s pipeline trajectory, Sharpington also noted the importance of collaboration in this field. ”The collaboration with Merck has been hugely beneficial in our immune-oncology development program. We have also benefited from an earlier research collaboration with Genentech in inflammatory bowel disease that provided useful insight into that condition. As a small company, these partnerships are very valuable, providing validation and endorsement as well as being a source of data and information and potentially a commercial partner for our products.”

Like Microbiotica, most companies in the microbiome therapeutic space aren’t biotech giants, meaning these more established companies will also have an important role to play in bringing these solutions to market.

The understanding of the mechanisms by which the microbiome exerts its effect on the human immune system is growing and according to Sharpington, it has the potential to tone the immune system and to regulate the gut epithelial barrier, disruption of which is the source of inflammation in many disease conditions.

“These multiple mechanisms, combined with a benign safety profile, have therapeutic potential in a number of indications either as stand-alone or combination treatments. In inflammatory diseases, we have the potential to develop disease-modifying LBPs, increasing periods of disease remission, by treating the underlying causes of inflammation.”

While Sharpington already mentioned that he believes the next steps for microbiome modulation will be toward more specifically targeted therapeutics, there are still challenges that need to be addressed.

“On a practical note, we are also learning how to design, manufacture, and develop these novel therapeutics. As this is still a novel modality, we do need to work as a community with regulatory agencies to develop guidelines on how best to develop and regulate the approval of these exciting new medicines,” said Sharpington.