Abstract
BACKGROUND: The discovery and therapeutic application of immune checkpoint inhibitors (ICIs) have 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 overcoming resistance to immunotherapy. METHODS: This study (NCT04130763) is an open-label, single-arm, single-center, phase I study assessing the safety and efficacy of fecal microbiota transplantation (FMT) from healthy donors in 10 patients with advanced GI cancer resistant to anti-programmed death-ligand 1 (PD-(L)1) treatment. 10 patients with histologically confirmed, unresectable, or metastatic GI cancers (8 gastric, 2 colorectal) who were refractory to anti-PD-(L)1 treatment were enrolled. Patients received initial FMT treatment via oral capsules (60 capsules), followed by a combination therapy phase, where maintenance FMT (10 capsules per treatment) was paired with nivolumab at 3 mg/kg every 2 weeks for six cycles. Serial biomarker assessments were conducted through both fecal and blood sampling. RESULTS: The combination of FMT and anti-PD-1 treatment was well tolerated with no serious adverse events. The objective response rate was 20% and the disease control rate was 40%. Clinical benefits were associated with colonization of donor-derived immunogenic microbes, and an activated immune status reflected by peripheral immune cell populations. Moreover, microbial signatures were identified for anti-programmed cell death protein-1 (PD-1) responsiveness and validated in an independent cohort. CONCLUSIONS: This phase I study demonstrates the feasibility and safety of combining FMT with anti-PD-1 therapy in patients with ICI-refractory gastric cancer. The observed preliminary efficacy signals and identified microbial signatures generate hypotheses for future trials to investigate microbiome-based approaches to enhance immunotherapy efficacy. TRIAL REGISTRATION NUMBER: NCT04130763.