Donor-derived regulatory dendritic cell infusion and early immunosuppressive drug withdrawal in living-donor liver transplantation: a phase I/IIa trial

Operational tolerance (OT) following complete immunosuppression withdrawal (ISW) is rare ( ~ 13%) in eligible adult liver transplant recipients when initiated 1-2-years post-transplant. Regulatory dendritic cells (DCregs) promote transplant tolerance in pre-clinical models and attenuate immune effector cells in humans. Here, we completed a first-in-human phase I/IIa trial (2-year recruitment; 5 ± 0.5 years follow-up) to evaluate the feasibility, safety and preliminary efficacy of pre-emptive donor-derived DCreg (ddDCreg) infusion 7-days pre-transplant in 15 prospective living-donor liver recipients. Two patients were excluded from analysis for reasons unrelated to the study. ISW began one year post-transplant in candidates with a quiescent/permissive protocol biopsy. ddDCreg infusions were safe, reproducible, and well-tolerated. One-year post-transplant, 8/13 patients were eligible for ISW, 4 achieved complete ISW, 3 remained off all immunosuppression for >1 year. These 3 remained drug-free for 3.0 ± 0.17-years, reflecting a 37.5% OT rate in ISW-eligible recipients. Given the exploratory nature of this trial, additional studies to evaluate efficacy are needed. ClinicalTrials.gov registration number NCT03164265 Reducing or stopping immunosuppression in recipients of allografts has the potential to spare them from increased risk of infection, malignancy and cardiovascular events. Here, the authors report the results of a phase-I clinical trial evaluating the use of donor-derived dendritic cells as means to achieve operational tolerance in living-donor liver transplantation.