Links between the health and diversity of the gut microbiome and immune response have been proposed for many years. More recently, response to immunotherapy has also been associated with the health and composition of the gut microbiota, with multiple studies identifying differences between the microbiota of responding versus non-responding patients undergoing treatment with immune checkpoint inhibitors. As evidence continues to implicate the gut microbiome in immunotherapy response, key questions arise regarding how this knowledge can be used to guide treatment decisions and enhance therapeutic responses in all patients.
Research published last month in Science by Spencer and colleagues from the University of Texas MD Anderson Cancer Centre found that melanoma patients receiving treatment with immune checkpoint inhibitors and reporting adequate daily fibre intake achieve significantly longer progression-free survival compared with those who consume less than 20g of fibre a day. In addition, the researchers also report a link between the consumption of probiotic supplements and disease progression, with the most favourable outcomes observed in those patients with high fibre and low probiotic intake. This research complements earlier studies, which have found the use of antibiotics can hinder response to immunotherapy and that improved responses in melanoma patients can be associated with the presence of specific bacteria in the gut.
Data presented at the Gastrointestinal Cancers Symposium this month from the DELIVER trial have also highlighted the potential for using the gut microbiome to predict which patients may be at risk of certain side effects caused by immunotherapy. In patients with gastric cancer receiving Bristol-Myers Squibb’s (BMS) Opdivo (nivolumab), the prevalence of adverse skin-related events was found to be associated with certain bacteria; specifically, those patients presenting with Arthrobacter and pathways associated with fatty acid metabolism were found to experience more side effects than patients who did not harbour this genus.
Immunotherapy has proven to be transformative in numerous solid tumour indications. Despite this, a substantial percentage of patients either do not respond to these or see only limited benefit, necessitating a switch to alternative therapies. In many indications, no such alternatives exist. It is clear that the gut microbiome can have a significant impact on the immune system and, by extension, a patient’s response to immunotherapy. As understanding of the interplay between the microbiome and immune system grows, it may be possible to improve responses by harnessing the microbiome’s potential; indeed, numerous companies are developing bacterial therapies that aim to replicate the effects of ‘good’ bacteria.
Several trials are now underway combining bacterial therapies with immunotherapies. These include a Phase I trial from Synlogic, whereby its experimental agent is injected directly into tumours and is being combined with Roche’s PD-L1 inhibitor Tecentriq (atezolizumab); a Phase I/II trial from 4D Pharma, investigating the efficacy of its live biotherapeutic in combination with Merck’s Keytruda (pembrolizumab); and a Phase I trial from Vedanta Biosciences, investigating its candidate with Opdivo. These trials are being carried out in patients with a range of solid tumours. This approach could offer hope to the significant number of patients who would otherwise see limited responses to immune checkpoint inhibitors.