Upfront fecal microbiota transplantation for the management of immune checkpoint inhibitor mediated diarrhea and colitis

Introduction : Immune checkpoint inhibitors have revolutionized cancer therapy; however, adverse events from an unchecked immune system such as immune checkpoint inhibitor mediated diarrhea and colitis (IMDC) can develop. Fecal microbiota transplantation (FMT) remains an option for patients with refractory colitis, but has not been tested in an upfront setting. Methods : From an open-label, phase I/II clinical trial (NCT0403861) starting June 2021, we report an analysis of adult patients with IMDC treated with upfront FMT. We performed fecal shotgun metagenomic sequencing, metabolomic, transcriptomic and immunofluorescence profiling pre-FMT and post-FMT and and plasma biomarkers of inflamamtion and immune response pre-FMT to predict response. Results : 13 patients were treated with FMT, of which 11 (84.6%) achieved clinical response with a median time to clinical improvement of 1(1-5) days. Among responders sequenced with baseline and follow-up (n = 8), 6 patients (75%) had an increase in alpha diversity post-FMT. Notably, in responders Lacrimispora amygdalina and Alistipes shahii increased independently at both 2 and 4 weeks post FMT. Interestingly, aspartic and propionic acid decreased post-FMT (p < 0.05). Using multiplex immunohistochemical immunofluorescence staining of samples obtained at presentation, we determined that total CK+ and CK+Ki67+ cell populations were reduced in non-responder patients. Additionally, there was a trend toward lower pre- and post-FMT CD20+, CD20+Ki67+, CD4+FOXP3+, and CD8+FOXP3+ cell populations in non-responder patients. Immune cell-type abundance scores showed increased plasma cells, neutrophils, (M1 and M2) macrophages, memory activated and resting memory CD4+ T cells , CD8+ T cells,T follicular helper (Tfh) cells, regulatory T cells (Treg), in pre-FMT samples which all decreased dramatically in post-FMT samples, likely related to response to FMT. Non-responders had lower baseline plasma GDF2, TLR3, CCL22, and FGF21 and higher baseline plasma CXCL14, OSM, IL-1β and IFNG. Conclusion : FMT is a promising front-line therapeutic option for patients who develop IMDC with high efficacy and favorable safety profile. Additional microbiome, blood and tissue analysis provides insights in future directions of potential mechanisms and targets for development of novel therapeutic intervention.