Fecal microbiota transplantation promotes immunotherapy sensitivity in refractory gastrointestinal cancer patients: open label, single-arm, single center, phase 1 study

Abstract Background The discovery and therapeutic application of immune checkpoint inhibitors (ICIs) has significantly improved clinical outcomes in cancer treatment. However, the response rate is still low in gastrointestinal (GI) cancers. The gut microbiome’s impact on immune modulation is a promising area for enhancing ICI efficacy. Methods This study ( NCT04130763 ) is an open label, single-arm, single center, phase 1 study assessing the safety and efficacy of fecal microbiota transplantation (FMT) from healthy donors in ten advanced GI cancer patients resistant to anti-PD-(L)1 treatment. Patients received initial FMT treatment via oral capsules, followed by a combination therapy phase, where maintenance FMT was paired with nivolumab at 3mg/kg every two weeks for six cycles. Serial biomarker assessments were conducted through both fecal and blood sampling. Findings The combination of FMT and anti-PD1 treatment was well tolerated with no serious adverse reactions observed among all 10 patients. The objective response rate was 20% and the disease control rate was 40%. The progression-free survival of these two responders were 15 and more than 19 months respectively. Clinical benefits were associated with colonization of donor-derived immunogenic microbes, and an activated immune status reflected by peripheral immune cell populations. Responder-enriched microbes interacted closely as a butyrate-functional guild, while non-responder-enriched microbes interacted sparsely and had higher fraction of oral-originated microbes. Donor-specific microbial traits that influence clinical efficacy of FMT were validated in an independent cohort. Interpretation The current study demonstrates the feasibility of FMT for ICI-refractory GI cancer patients and provides a foundation for live biotherapeutic product (LBP) development to enhance ICI efficacy.