MICA: Microbiota Transplant Prior to Allogeneic Stem Cell Transplant (MAST) study

The microbes which inhabit our gut play a pivotal role in our health, influencing the immune system, response of a patient to drugs and progression of many diseases. Blood cancer patients frequently become colonised with (or 'carriers' for) bacteria in different areas of the body (including their gut lining) that are resistant to nearly all the known antibiotics that we have; these bacteria can enter the bloodstream and cause severe infections that are hard to treat. This situation arises because these patients are frequently prescribed antibiotics to control and treat infections, as well as because of the chemotherapy they receive. In healthy individuals, the many health-associated gut microbes we have can protect against colonisation by antibiotic resistant bacteria , but this function is severely compromised in blood cancer patients due to the many courses of antibiotics that they have received during their disease.

Since the antibiotics that we have cannot kill these pathogens in the cancer patients, we developed an alternative treatment that transplants the gut microbes from healthy individuals into the intestines of blood cancer patients who are colonised with antibiotic resistant bacteria. When we undertook this procedure, our primary goal was to control the number of antibiotic resistant bacteria. However, the haematologists also unexpectedly noticed that their patients were responding to their bone marrow transplant treatment better than the patients who had not received gut microbes transplantation. We found that the blood cancer patients who had received a gut microbes transplantation were less likely to need further antibiotics during treatment. Furthermore, none of them were admitted to intensive care, they had fewer days in hospital, fewer cases of fever, and better long-term success of their stem cell transplant. These changes in their response to the bone marrow transplant spurred us to consider whether a gut microbes transplantation in patients with leukaemia before they receive their bone marrow transplant will improve the patient's journey during treatment for their cancer.

To test this idea further, we will conduct a randomised placebo-controlled clinical trial. We will randomise blood cancer patients to receive either a capsule containing gut microbes from a healthy donor or a placebo capsule before they receive their bone marrow transplant. 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 stem cell 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.

The bacterial component of the gut microbiome is a key driver of host health and immune function. In cancer patients, particularly those with haematological malignancies, the gut microbiota is significantly altered by a number of factors; including repeated courses of broad-spectrum antibiotics used to treat neutropenic fevers and chemotherapies used in haematopoietic stem cell transplant (HSCT) conditioning regimens. These therapies lead to intestinal inflammation and much lower diversity of both bacterial and fungal organisms, which is strongly associated with a higher mortality in patients receiving HSCT (PMID: 32101664 and 34282272). Additionally, the repeated exposure to antibiotics can lead to the emergence or overgrowth of multidrug-resistant organisms (MDRO) that colonise the gut. Colonisation by Gram negative MDROs leads to higher rates of bloodstream infections, which are often challenging to treat, and is associated with higher rates of intensive care support and higher mortality.

Recently, we employed intestinal microbiota transplant (IMT) in a cohort of patients colonised with MDROs prior to HSCT, delivered via nasogastric tube. We observed that administration of just 1-2 IMTs per patient was overall safe and well tolerated, and in a retrospective analysis, associated with fewer bloodstream infections (MDRO-related, and non-MDRO related), and improved clinical outcomes, including reduced mortality (PMID: 32681643 and 34513724).

During the course of our compassionate use programme, it became clear that the benefits of IMT are likely not restricted to those with MDRO, but potentially have broader impact in all patients undergoing HSCT who have received pre-HSCT chemotherapy and antibiotics. To explore this further, we therefore propose a phase IIa double-blind placebo controlled randomised clinical trial of IMT in HSCT patients, using a novel oral/capsulised formulation, thus avoiding the drawbacks of invasive administration regimens.