Efficacy of fecal microbiota transplantation in patients with anti-PD-1-resistant/refractory gastrointestinal cancers.

389 Background: Gut microbiome that changed the response to anti-PD-1 therapy (aPD-1) against melanoma by fecal microbiota transplantation (FMT) has been reported. To investigate whether resistance to aPD-1 against gastrointestinal (GI) cancers can be overcome by FMT, this single arm, open label, investigator-initiated trial explored the efficacy of combination of FMT + nivolumab in patients with aPD-1 resistant/refractory (aPD-1r)-GI cancers. Methods: Ten patients were planned to be enrolled. Interim analysis was planned when at least one patient demonstrated effective outcome. FMT capsules were from healthy donors. FMT capsules (CFU≥1×10 12 ) were administered in the first week. Nivolumab (3mg/kg, q2w) combined with a maintenance dose of FMT capsules (CFU≥1.5×10 11 ) were started at Week 2 and continued for 6 cycles or until progress of disease (PD) after 3 cycles of treatment. If patient responded to the treatment and would be benefit from the treatment beyond 6 cycles, patients would enter the Expended Excess Program to continue the therapy. RECIST v1.1 evaluation was performed every 3 cycles. Stool samples were collected every 2 weeks for metagenomic analysis of gut microbiota. Results: 8 aPD-1r patients were enrolled and finished the study by the time of this analysis. Nivolumab + FMT therapy was well tolerated. No serious adverse reaction was observed. 8 patients completed 3 cycles of treatment. Metagenomic analysis of gut microbiota from Responders (R) and Non-Responders (NR) groups revealed the gut microbial composition of R group is significantly closer to that of the donor than NR group, which indicated much better colonization of donor microbiota in R. Alpha diversity was significantly higher in R than that in NR, along with a set of differential bacterial species and biological process functions including dTMP biosynthetic process enriched, suggesting gut microbiome’s potential role in the treatment. The flow cytometry analysis indicated a significant increase of IFN-ϒ+ cells in PBMCs in R at Day 8 after FMT (the highest increase during the study), before combination therapy had started. A significant increase in Ki-67+ cells in PBMCs was also observed in the R group. Relative abundance of differential bacterial species enriched in R were found to be significantly negative correlated with tumor markers like CA199 and tumor volume, and some were positively correlated with expression of CD3+CD4+ cells and CD3+CD8+ cells. Conclusions: FMT+aPD-1 may overcome the resistance to aPD-1 against GI cancer via changing gut microbiota structure. Trial registration number: NCT04130763. Keywords: gastrointestinal cancers; fecal microbiota transplantation; anti-PD-1 therapy. Clinical trial information: NCT04130763 .