Dose-escalation studies of mesenchymal stromal cell therapy for decompensated liver cirrhosis: phase Ia/Ib results and immune modulation insights

Abstract

Abstract Decompensated liver cirrhosis (DLC) is characterized by severe liver dysfunction and immune dysregulation, posing significant treatment challenges. Mesenchymal stromal cell (MSC) therapy has shown promise in DLC treatment, but the optimal dosing strategies and dose-dependent therapeutic mechanisms in humans remain unclear, limiting its clinical application. We conducted sequential Phase Ia/Ib trials using a single-arm, dose-escalation design to evaluate the safety and tolerability of MSC therapy in DLC patients while also exploring its immunomodulatory effects and gathering preliminary therapeutic signals. In Phase Ia, four dose cohorts received a single dose of MSCs: 5.0 × 10⁷, 1.0 × 10⁸, 1.5 × 10⁸, and 2.0 × 10⁸ cells. Patients were followed up on Days 3, 7, 14, and 28. Multiomics analyses, including single-cell RNA sequencing and cytometry by time of flight, were conducted to perform exploratory mechanistic analyses investigating immune cell dynamics and dose-dependent responses. Building on these findings, Phase Ib included two dose cohorts, each of which received three doses of MSCs administered one week apart: 1.0 × 10⁸ and 2.0 × 10⁸ cells per dose. Patients were followed up on Days 7, 14, 21, and 28 to further evaluate the safety and feasibility of multiple-dose regimens. The trials were registered at ClinicalTrials.gov (NCT05227846 and NCT05984303). MSC therapy demonstrated good safety and tolerability in both Phase Ia and Phase Ib trials, with no severe adverse events, dose-limiting toxicities, or serious unexpected adverse reactions observed up to Day 28. Multi-omics analyses revealed that higher MSC doses elicited stronger immunomodulatory effects, particularly by modulating monocyte subsets. In particular, myxovirus resistance 1 positive (MX1 + ) monocytes, a key monocyte population, exhibited dose-dependent changes and were identified as a mediator of MSC-induced immunomodulation. These effects were sustained for up to seven days post-treatment but diminished by Day 14. Preliminary clinical signals included improvements in Child–Pugh scores, Model for End-Stage Liver Disease scores, liver function markers, and quality-of-life metrics, particularly in the higher-dose and multiple-dose groups. This study demonstrates the safety and tolerability of MSC therapy in patients with DLC and provides the first human-based evidence on the dose‒effect relationship and optimal administration regimens. The identification of MX1 + monocytes as a critical mediator highlights the potential of MSC therapy to modulate immune dysfunction in DLC. These findings offer valuable insights for optimizing MSC therapy and informing the design of future efficacy-focused clinical trials.