Fecal microbiota transplantation plus immunotherapy in non small cell lung cancer and melanoma

The MT-LUMINate phase 2 trial, recently published on Nature Medicine, showed a good objective response rate in patients with non small cell lung cancer (NSCLC) and melanoma treated with a fecal microbiota transplantation plus immunotherapy, suggesting that elimination of deleterious taxa is required for  microbiota transplantation-mediated therapeutic benefit.

Over half of patients with NSCLC or melanoma treated with immunotherapy exhibit primary resistance, but fecal microbiota transplantation may overcome resistance to anti PD-1 therapies: thus, the FMT-LUMINate phase 2 trial assessed healthy donor fecal microbiota transplantation plus anti-PD-1 in NSCLC or anti-PD-1 plus anti-CTLA-4 in melanoma, in the first-line setting. A total of 40 patients were involved and received a single fecal microbiota transplantation via oral capsules prior to immune checkpoint inhibitors initiation. Results showed that in NSCLC, the objective response rate was 80%, in melanoma it was 75%; microbiota transplantation was deemed safe in both cohorts. Analysis of post-transplantation microbiome showed that responders exhibited significantly greater loss of baseline bacterial species compared to non-responders, with frequent depletion of Enterocloster citroniae, E. lavalensis and Clostridium innocuum. As authors add, «Our results suggest that clinical benefit from fecal microbiota transplantation is not mediated by the number of specific donor-derived strains. By contrast, clinical responses were associated with a robust pattern of depletion of several deleterious bacterial species. In our study, when reintroduced into tumor-bearing mice after oral gavage of favorable fecal microbiota transplantation, these harmful bacteria led to anti-PD-1 resistance. These findings suggest that therapeutic response of fecal microbiota transplantation may result from the elimination of immunosuppressive pathobionts. These results offer an actionable framework for donor selection, biomarker development and design of next-generation microbial therapies aimed at selectively eliminating immunosuppressive pathobionts», they conclude.