Fecal microbiota transplantation as a mean of overcoming immunotherapy-resistant cancers – hype or hope?

Abstract

Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). The gut microbiota has co-evolved with humans for millions of years, creating a complex network of regulations and reciprocal effects.1,2 However, these networks have been exposed only in the recent decades, thanks to the ability to sequence bacterial genomes and to the technical revolution during the 2000s which turned DNA sequencing into an affordable and feasible lab tool.1,3,4 Today, the gut microbiota is known to affect not only local inflammatory processes in the gut5 but also systemic processes such as obesity and diabetes,6 pregnancy,7 autism8 and neuro-degenerative diseases.9,10 The gut microbiota also affects the immune system. This interaction is so significant that the gut microbiota is essential for the proper development of lymphoid organs and the adaptive immune system.11 However, the presence of microbes in our gut is not merely an immune “on–off switch”, as different microbes can suppress or promote different immune cells, dynamically shaping the overall function of our immune system.12 Based on these findings, several groups have examined a potential association between the gut microbiota and clinical response to cancer immunotherapy, especially to immune checkpoint inhibitors (ICIs). All groups demonstrated clear microbiota compositional differences between ICI responders and non-responders.13–17 Since the gut microbiota can dynamically shape our immune system, it is intuitive to assume that replacing a patient’s gut microbiota into a more “ICI-favorable” composition will enhance overall ICI effectiveness. Indeed, two clinical trials recently demonstrated that combining fecal microbiota transplantation (FMT) from donors who responded to ICIs into recipient patients with metastatic ICI-resistant melanoma, coupled with ICI re-induction, resulted in objective clinical response rates of ~30%.18,19 Patients who responded to the combination of FMT and ICI had increased intra-tumoral infiltration of CD8+ T-cells, T-helper type 1 cells and antigen presenting cells while infiltration of myeloid derived suppressor cells decreased.18,19 These intra-tumoral immune changes are well-established as ICIfavorable features20,21 and were consistently reported in in pre-clinical models of microbiota modulation.22 Albeit limited by small sample sizes, the fact that two independent cancer centers in different parts of the world with different patient populations (primary and acquired ICI failures18,20 versus only primary ICI failures19,20) using different ICIs (nivolumab18 versus pembrolizumab19) reported similar clinical and translational results in accordance with pre-clinical findings is highly supportive of the validity of these preliminary results.