Safety and feasibility of third-party multipotent adult progenitor cells for immunomodulation therapy after liver transplantation--a phase I study (MISOT-I)

Abstract

Background: Liver transplantation is the definitive treatment for many end-stage liver diseases. However, the life-long immunosuppression needed to prevent graft rejection causes clinically significant side effects. Cellular immunomodulatory therapies may allow the dose of immunosuppressive drugs to be reduced. In the current protocol, we propose to complement immunosuppressive pharmacotherapy with third-party multipotent adult progenitor cells (MAPCs), a culture-selected population of adult adherent stem cells derived from bone marrow that has been shown to display potent immunomodulatory and regenerative properties. In animal models, MAPCs reduce the need for pharmacological immunosuppression after experimental solid organ transplantation and regenerate damaged organs.

Methods: Patients enrolled in this phase I, single-arm, single-center safety and feasibility study (n = 3-24) will receive 2 doses of third-party MAPCs after liver transplantation, on days 1 and 3, in addition to a calcineurin-inhibitor-free "bottom-up" immunosuppressive regimen with basiliximab, mycophenolic acid, and steroids. The study objective is to evaluate the safety and clinical feasibility of MAPC administration in this patient cohort. The primary endpoint of the study is safety, assessed by standardized dose-limiting toxicity events. One secondary endpoint is the time until first biopsy-proven acute rejection, in order to collect first evidence of efficacy. Dose escalation (150, 300, 450, and 600 million MAPCs) will be done according to a 3 + 3 classical escalation design (4 groups of 3-6 patients each).

Discussion: If MAPCs are safe for patients undergoing liver transplantation in this study, a phase II/III trial will be conducted to assess their clinical efficacy.

Figure 1

Dose-limiting toxicity (DLT) events.Clinical events of toxicity related to MAPC infusions. If more than one DLT event occurs in a dose cohort, the study will be stopped.

Figure 2

Dose escalation design. Three patients will be treated with the starting dose. If no DLT occurs, the next cohort will be treated with the next MAPC dose level. If one DLT occurs in a cohort, a second cohort of 3 patients will be treated with the same MAPC dose level. The study will be stopped if more than one DLT event is recorded after enrolling at most 6 patients.

Figure 3

Inclusion and exclusion criteria of the study.

Figure 4

Immunosuppressive treatment regimen. Basiliximab will be applied on days 1 and 5 after transplantation; 2 g mycophenolic acid (MPA) will be applied per day given as a split dose. Steroids will be started on postoperative day 1 and tapered by month 6 after liver transplantation, MAPC infusions will be administered into the portal vein during transplantation and later intravenously on day 3.