Potential for faecal microbiota transplantation to enhance immunotherapy in advanced melanoma

11th July 2023

A faecal microbiota transplantation (FMT) from healthy donors prior to PD-1 inhibitor immunotherapy could represent a novel and effective approach to the management of advanced melanoma, according to a recent phase 1 trial.

Published in the journal Nature Medicine, researchers combined healthy donor FMT with the PD-1 inhibitors nivolumab or pembrolizumab in previously untreated patients with advanced melanoma.

The primary outcome of interest was safety, with key secondary endpoints of the objective response rate, changes in gut microbiome composition and systemic immune and metabolomics analyses.

A total of 20 patients with a confirmed diagnosis of unresectable or metastatic cutaneous melanoma and with no previous anti-PD-1 treatment were enrolled.

Patients received a single FMT via capsules containing 80-100 mg of faeces from heavily screened healthy donors. Individuals were required to consume 36-40 capsules under supervision followed by a 30-minute period of observation.

Faecal microbiota transplantation ‘safe and effective’

When considering the primary outcome, eight patients experienced grade 1-2 FMT-related toxicities, mainly diarrhoea, flatulence and abdominal discomfort. However, there were no grade 3 or higher adverse events before receipt of the first dose of anti-PD-1 therapy.

The objective response rate was 65% and this included four patients who experienced a complete response. Microbiome profiling revealed that all of the patients engrafted strains from their respective donors although the acquired similarity between microbiomes increased over time in responders.

The researchers concluded that FMT from healthy donors represents a safe new therapeutic tool that has clinical potential and should be explored further in randomised trials.

Additional approaches are needed in advanced melanoma given that five-year survival even with combination immunotherapy is just over 50%. Previous work suggested that FMT and anti-PD-1 therapy, could overcome resistance to anti-PD-1.

Faecal microbiota transplantation beneficial in advanced cirrhosis

28th June 2023

Using faecal microbiota transplantation in patients with advanced cirrhosis improves gut flora microbiota and ammonia metabolism, according to a feasibility trial by UK and Swedish researchers.

Data from the prospective, randomised placebo controlled feasibility trial of faecal microbiota transplantation (PROFIT) trial was presented at the European Association for the Study of the Liver (EASL) 2023 congress.

Gut flora and bacterial translocation play an important role in the pathogenesis of the complications of cirrhosis such as hepatic encephalopathy (HE). The antibiotic rifaximin reduces the risk of HE recurrence and HE-related hospitalisations in cirrhosis, possibly through its effects on metabolic function of the gut microbiota and a reduction in ammonia-producing bacteria.

But whether faecal transplantation, by modifying the gut microbiota, could benefit those with cirrhosis is unclear and this was the subject of an abstract (GS-007) presented at the congress. For the study, 50 g of frozen faecal microbiota transplants (FMT) were administered into the jejunum via endoscopy in a ratio of 3:1 (FMT vs placebo). The study was single-blind, so only the investigators were aware of the intervention received by patients. Blood and stool samples were collected at baseline and then after seven, 30 and 90 days.

Faecal transplantation in advanced cirrhosis

A total of 32 patients were included in the study. FMT significantly reduced the stool carriage of Enterococcus faecalis and other pathobionts. There was also a significant reduction after 30 days in plasma ammonia (p = 0.0006), with a corresponding higher faecal ammonia (p = 0.011) in the FMT group compared to placebo.

In addition, after 30 days, there was enhancement in the enzymes required for nitrogen assimilation and excretion via the urea cycle, with greater secretion of urinary hippurate (p = 0.0299) in the FMT group.

It was also clear that the use of FMT reduced biomarkers of inflammation but increased biomarkers for gut barrier repair.

The researchers concluded that their data supported a role for FMT in patients with cirrhosis.

Following the PROFIT trial, the same group are about to embark on the PROMISE trial, in which patients with cirrhosis take capsules containing dried stool from a healthy donor, rather than via endoscopy as in the PROFIT trial.

A recent Cochrane review found that faecal transplantation improves clinical and possibly endoscopic remission in ulcerative colitis.