Why we are carrying out this study

The bacteria which inhabit the gut play important roles in our health, they influence how the immune system works, how patients react and respond to drugs, and how diseases progress.  However, they can also cause infections of the blood, and in blood cancer patients this leads to serious problems.  Treating these blood infections with antibiotics, over time, results in these bacteria becoming resistant to the antibiotics and this causes even more problems, as they can no longer be treated. The antibiotics used to treat the blood infections also kill off the patient’s gut bacteria and so the roles they play, for example, ensuring your gut wall is healthy and intact, and supporting your immune system are also affected. This study will explore an exciting new treatment to reset the gut bacteria to help blood cancer patients during their bone marrow transplant.

The research so far

We have been investigating a new method of preventing these bacteria causing infections.  We have developed an oral capsule which is an ‘intestinal microbiota transplantation’ or IMT.  This IMT capsule is produced by taking some of a stoolfrom a healthy person (who has passed an extensive health screen before donating), processing this in a laboratory to extract the ‘beneficial’ bacteria then transplanting this into the gut of the blood cancer patient via the oral capsule.  This new treatment has worked well in patients who’ve had it up to now, was safe, and helped to reduce the infections they experienced during their blood cancer treatment.

Moreover, the haematologists have reported that the patients who received the IMT seemed to be doing much better more generally after their bone marrow transplant, when compared to patients who had not had an IMT.  They believed that the IMT was having a much more profound impact on the patient and their recovery after their bone marrow transplant.  This exciting observation needed to be tested further, rather than in a one-by-one study of patients.  The MAST study will now explore this novel treatment.

How we will do this – for trial participants

We will conduct a clinical trial of IMT in blood cancer patients who are about to receive a bone marrow transplant. We will randomise blood cancer patients to receive either a capsule containing gut microbes from a healthy donor or a placebo (i.e. ‘dummy’) capsule before they receive their bone marrow transplant. We are aiming to ‘prehabilitate’ the gut microbes, which have been severely affected by the courses of chemotherapy and antibiotics, using the IMT.

When we say prehabilitating the gut, we mean we are trying to reset the composition of the gut microbes back to what it was before all drugs and treatments were given.  We will compare the diversity (degree of mixture) of the microbes in their gut, between the two groups over time, as low gut microbe diversity has been shown to predict blood cancer patients having more problems after their bone marrow transplant. We will also compare how patients in each group respond to their treatment, any safety issues, and whether any extra treatment or care is required.  In the long term this study of IMT in 50 patients will help us determine if we should conduct a much larger study, over a longer period, to see if we can improve the survival and quality of life of bone marrow transplant patients using capsule IMT.

Introduction

Whilst it has been long established that opportunistic infections occurring during periods of chemotherapy-associated neutropenia, it is thought they often arise from translocation of intestinal commensal organisms. To date, the full role of the intestinal microbiota in outcome from haematopoietic stem cell transplant (HCT) in patients with haematological malignancy has been hugely underappreciated.

The development of next generation microbial sequencing techniques (e.g. 16S rRNA gene sequencing and shotgun metagenomics) has demonstrated just how diverse the intestinal microbiota is in healthy subjects. The evolving high throughput ‘multi-omic’ systems biology techniques (including proteomics and metabolomics) are starting to unravel how critical the gut microbiota is to health, gut barrier function, the immune system and gene expression and the impact of disrupting it has on all these features.

In health, the intestine is home to a vast array of microbes termed the microbiota. This microbiota has a dynamic symbiotic relationship with their host, and together with reciprocal interactions with their host environment, result in a balanced, diverse microbiota.  The microbiota impacts on nutrition, pathogen resistance and immune development, all of which play key roles in the success of HCT.

Whilst there are a number of metrics of microbiome health, microbiota diversity is straightforward to measure, and is considered a robust surrogate for gut microbiome health. Large scale profiling of intestinal microbiota samples during HCT has recently shown that reduced diversity during HCT is associated with poorer overall survival.

This survival difference is likely to be multifactorial, derived from differences in infections, nutrition, and immune reconstitution. Whilst some of these factors (such as pathogen resistance, infections, and nutrition) have the potential to impact on early non-relapse mortality, others (and particularly immune reconstitution) may have impact on the longer-term modulators of HCT, such as immune tolerance and graft versus host disease.

Intestinal Microbiota Transplantation

Intestinal microbiota transplantation (IMT) has the potential to increase the diversity in a low diversity microbiota, and has an established role in the management of recurrent Clostridioides difficile infection (rCDI).  The reduced microbiota diversity observed in the setting of rCDI occurs because of broad-spectrum antibiotic use and can be restored to the level of healthy donors with one or two treatments as rapidly as within 72 hours. The remarkable clinical responses, in up to 90% of patients, has led to exploration of this therapy in other settings where disruption of the microbiota composition has been observed, such as inflammatory bowel disease or cirrhotic liver disease and a number of clinical studies are ongoing in the immune-oncological therapies as well, e.g. response to anti PDL1 biologics for some cancers.

The observation that the intestinal microbiota frequently serves as a reservoir for multidrug-resistant organism (MDRO)-mediated infections, coupled with the suggestion that the predominance of MDROs within the intestinal niche reflects a global reduction in microbiota diversity, has led several groups to employ IMT as a novel biological approach to rescue the microbiota. In this context, while IMT may not eradicate MDRO, restoration of a more diverse microbiota reduces the incidence of clinical infections, reinforcing the impact of reduced diversity.

A striking observation in many of the IMT studies reported in immunocompromised patients is the safety and tolerability profile of the intervention, even with marked immunocompromise/ immunosuppression, and this profile has been supported with systematic review evidence; as such, current IMT guidelines support the use of IMT within such populations, albeit with certain additional caution (including consideration of the use of CMV and EBV-negative donors).

We have previously used IMT prior to HCT in patients with MDRO colonisation. Patients with a history of MDRO colonisation, or a history of MDRO-mediated clinical infections were offered IMT initially as part of a compassionate-use programme, and later as part of a cohort study. Patients whose infections pre-dated access to a compassionate use program, or who declined participation in the program, had a high incidence of MDRO-infections during HCT, as well as a high incidence of intensive care unit admission, and non-relapse mortality. By comparison, those undergoing IMT had fewer days of fever, zero episodes of ITU admission, and a significantly better survival.

Rationale for the study

While MDRO colonisation may represent an extreme phenotype of a perturbed microbiota, skewed intestinal dominance, and depletion of obligate anaerobes resulting from antimicrobial use is associated with an increased incidence of blood stream infections (BSI) in HCT recipients. Furthermore, most patients undergoing HCT have received prior courses of neutropenia-inducing chemotherapy, which is associated with intestinal mucosal damage, recurrent episodes of neutropenic fevers and further widespread use of broad-spectrum antimicrobials.

Chemotherapy, intestinal mucosal inflammation, and the use of broad-spectrum antibiotics are all risk factors for a perturbed, low diversity microbiota, meaning that few patients undergoing HCT have a healthy diverse gut microbiota at the time of HCT. IMT therefore offers the prospect of restoring intestinal microbiota diversity prior to HCT, with potential to reduce early treatment-associated complications such as BSI originating in the intestine and improve intestinal absorption.

The use of autologous IMT, harvested pre-HCT from the patient and delivered post-engraftment, to the same patient, has been tested in a single centre study. In this setting, IMT is delivered as a retention enema, and was reported to restore diversity, to pre-HCT levels, but follow-up for clinical endpoints, particularly GvHD and C. difficile infections, are ongoing. This approach however does not address the pre-existing skewed diversity immediately prior to transplant and excluded patients with a perturbed microbiota on the screening sample.

A phase 2 clinical study of allogeneic, healthy donor IMT, delivered post-HCT was terminated early after it emerged that donor screening had been inadequate, and two patients contracted extended-spectrum beta-lactamase (ESBL)–producing Escherichia coli bacteraemia originating from donor stool. Importantly, there are robust donor screening criteria in the UK that avoid this scenario if they are adhered to.

The method of optimal IMT delivery is also important. Early studies used duodenal delivery of cryopreserved slurry, while some groups prefer rectal retention enemas. However, both approaches are relatively invasive, and can deter patients from undergoing the procedure. The recent development of lyophilised capsule IMT has been shown to be equivalent to faecal slurry delivered endoscopically (at least in the context of rCDI) and is potentially more tolerable for patients (PPIE feedback).

In this trial we aim to explore the use of capsule IMT to restore microbiota diversity in the setting of HCT. While the primary focus of the study is restoration of intestinal diversity, the deliverability and tolerability of such a strategy at multiple UK sites will be a key focus. Furthermore, the trial will collect laboratory and clinical outcome data to inform subsequent larger clinical studies.

Find documents and videos to support your participation in the study.

• Professor Julian R. Marchesi – Co-Chief Investigator
• Dr Jiri Pavlu – Co-Chief Investigator
• Dr Ben Mullish - Co-Investigator
• Dr Andrew Innes - Co-Investigator
• Dr Frances Davies - Co-Investigator
• Dr Rohma Ghani - Co-Investigator
• Dr Graham Wheeler - Co-Investigator
• Mr Nicholas Johnson - Co-Investigator

Patient representatives

• Joanna Calder
• Anna Mamwell (Clinical Trials Patient Involvement Advocate)

• Dr Anjum B. Khan - Leeds Teaching Hospitals
• Dr Francesca Kinsella - University Hospitals Birmingham
• Dr Panagiotis Kottaridis - University College London Hospitals
• Dr Pramila Krishnamurthy - King’s College Hospital, London
• Dr Emma Nicholson - The Royal Marsden Hospital
• Dr Renuka Palanicawandar - Imperial College healthcare NHS Trust

• EnteroBiotix – the company who are supplying the capsule and placebo for the MAST study
• MRC - funding partner
• Dr Ben Mullish’s article on Intestinal Microbiota Transplantation