Longitudinal microbiome changes hold diagnostic value

For the first time, a study assessed longitudinal changes in microbiota during therapy with immune checkpoint inhibitors (ICIs).

Gut microbiome of advanced melanoma patients was profiled

Administration of ICIs augments T cell-mediated immune responses against tumors, resulting in improved overall survival of cancer patients at advanced stages. However, only a subset of patients shows durable responses. Recent research has shown that the intestinal microbiome might modulate responses to ICIs. Dr Johannes Björk (University Medical Center Groningen, the Netherlands) analysed longitudinal changes in the gut microbiome in response to immune checkpoint blockade (ICB) treatment from the observational PRIMM study (NCT03643289).

To this end, the gut microbiome was profiled of advanced melanoma patients (n=175) undergoing ICB at cancer centres in the UK and the Netherlands. Shotgun metagenomic sequencing was performed on stool samples to compare microbiome before and during treatment at up to 4 time points and to explore the correlation with treatment success, measured in terms of 12 months progression-free survival. 

Results confirmed that some of the previously reported microbial biomarkers at baseline (e.g. Faecalibacterium prausnitzii and Bifidobacterium longum) also increased longitudinally during treatment. However, these associations were often influenced by concomitant treatment characteristics. For example, microbiota differed between single ICB and combination ICB in patients that took no proton pump inhibitors (PPIs) and no antibiotics: Compared to non-responders, higher and increasing abundances of butyrate producers from the family Lachnospiraceae species were identified in responders on single ICB over the entire treatment period. “Of course, this is information we couldn´t know from previous baseline predictions only,” Dr Bjökr pointed out.

In contrast, non-responders were associated with higher and increasing abundances of several Bacteroides species, some of which have already been associated with non-responders in previous baseline studies.

PPI was associated with a Klebsiella pneumniae longitudinal increase in non-responders

Dr Björk also emphasised the effect of confounders like PPI use: PPI use was associated with a longitudinal increase in Klebsiella pneumniae in non-responders that was not seen in non-responders not taking PPIs.

Finally, the researchers compared longitudinal microbiota changes in responders who developed colitis compared with those who did not. In general, immunotherapy-induced colitis resembles the gut microbiome in inflammatory bowel disease. Bacteriodes caccae was enriched in responders that developed colitis compared with those who did not. Faecalibacterium prausnitzii, also a butyrate producer, was high and stable in responders resistant to colitis compared with those developing colitis. 

“I hope I could convince you that microbiome-based interventions should not solely rely on baseline biomarkers. This is key to increasing the efficacy of ICIs. We have to understand the dynamic of the system we want to modulate,” Dr Björn concluded.

  1. Hayase E, Jenq RR. Genome Med 2021;13:107.
  2. Björk J, et al. Longitudinal changes in the gut microbiome in response to immune checkpoint blockade. OP042, UEG Week 2022, Vienna, Austria, 8–11 October.