Safety and Tolerance of Immunomodulating Therapy With Donor-specific MSC in Pediatric Living-Donor Liver Transplantation

Study Overview
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Brief Summary
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Since the introduction of calcineurin-based immunosuppression, patient and graft survival in pediatric liver transplantation (LT) improved significantly. However, in contrast, calcineurin inhibitor (CNI) toxicity leads to significant morbidity and impairs quality of life for recipients. Moreover, CNI cannot prevent long-term allograft inflammation and fibrosis. Mesenchymal stem (stromal) cells (MSC) have potent immunomodulatory properties potentially promoting allograft tolerance and ameliorating toxicity of exposure to high dose CNI. Previous trials for non-solid organ transplant indications have shown an excellent safety profile of intravenous MSC application. The MYSTEP1 trial aims to investigate safety and benefits portal and intravenous MSC infusion in pediatric LT.

Detailed Description
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Background: Calcineurin inhibitors (CNI) have significantly improved patient and graft survival in pediatric liver transplantation (pLT). However, CNI toxicity leads to significant morbidity. Moreover, CNIs cannot prevent long-term allograft injury. Mesenchymal stem (stromal) cells (MSC) have potent immunomodulatory properties, which may promote allograft tolerance and ameliorate toxicity of high-dose CNI. The MYSTEP1 trial aims to investigate safety and feasibility of donor-derived MSCs in pLT. Methods/Design: 7 to 10 children undergoing living-donor pLT will be included in this open-label, prospective pilot trial. A dose of 1 × 106 MSCs/kg body weight will be given at two time points: first by intraportal infusion intraoperatively and second by intravenous infusion on postoperative day 2. In addition, participants will receive standard immunosuppressive treatment. Our primary objective is to assess the safety of intraportal and intravenous MSC infusion in pLT recipients. Our secondary objective is to evaluate efficacy of MSC treatment as measured by the individual need for immunosuppression and the incidence of biopsy-proven acute rejection. We will perform detailed immune monitoring to investigate immunomodulatory effects. Discussion: Our study will provide information on the safety of donor-derived MSCs in pediatric living-donor liver transplantation and their effect on immunomodulation and graft survival.

Official Title
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Safety and Tolerance of Immunomodulating Therapy With Donor-specific Mesenchymal Stem Cells in Pediatric Living-Donor Liver Transplantation, a 24-month, Non-randomized, Open-label, Prospective, Single-center Pilot Trial

Conditions
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Pediatric Liver Transplantation

Intervention / Treatment
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* Biological: Mesenchymal Stem Cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent (patients, both parents and / or legal guardian) age ≥ 8 weeks and ≤ 18 years undergoing living donor liver transplantation for chronic terminal liver failure Body weight > 5kg Exclusion Criteria: No suitability of the living-donor Pregnant or breastfeeding If appropriate: no use of adequate contraception Acute liver failure; highly urgent transplantations Receiving any form of solid organ retransplantation Multi-Organ-Transplantations Active autoimmune disease Pre-existing renal failure with eGFR < 50 ml/min/1.73 m2 or requiring hemodialysis Reduced pulmonary function (lung function test in children older than 6 years: FEV1 and FVC < 70% of age-appropriate norm) or clinical suspicion of pulmonary disease affecting patient's physical performance, requiring invasive or non-invasive mechanical ventilation. History of pulmonary embolism Pulmonary hypertension and / or right ventricular load in echocardiography Cardiac function: left ventricular shortening fraction (FS) < 25% Clinically significant systemic infections Critical care treatment like mechanical ventilation, dialysis or vasopressor agents. HIV seropositive, HTLV seropositive, Hepatitis B/C seropositive Hepato-biliary malignancies or history of any extra-hepatic malignancy Thrombophilia Budd-Chiari syndrome Pre-existent thrombosis of portal vein Doppler-sonographic evidence for relevant porto-systemic shunts, like persistent Ductus Venosus Cold ischemia time > 90 min Known abuse for drugs or alcohol Known allergy to DMSO

Ages Eligible for Study
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Minimum Age: 8 Weeks
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment with Mesenchymal Stem Cells<br>Two doses of 1 x 10^6 MSCs/kg body weight: first administration intraoperatively via intraportal infusion second infusion via intravenous infusion on postoperative day 2 (+/- 1 day) Standard immunosuppressive treatment consisting of steroids, basiliximab and tacrolimus according to the center's pediatric liver transplantation protocol | Biological: Mesenchymal Stem Cells<br>* Donor-specific, bone marrow derived mesenchymal stem (stromal) cells<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with MYSTEP-score grade 3 and grade 2 (toxicity of MSC infusion) | In order to evaluate and quantifiy acute clinical complications related to MSC infusion, the investigators defined the MYSTEP score, a specific pediatric infusional toxicity scoring system (adapted from MiSOT-I score). The score focusses on description of intraportal, pulmonary and systemic toxicity. For each of these three modalities, degrees of severity between 0 (no treatment emergent adverse event) and 3 (severe treatment emergent adverse event) have been defined. | 28 days | 
| Number of participants with occurrence of any severe adverse events (SAE) | A particular focus will be on viral infections and reactivation (ADV, HCMV, EBV, Hepatitis B, Hepatitis C and Hepatitis E), bacterial or fungal infections. | Two years | 
| Graft function after liver transplantation - Number of participants with abnormal liver tests | Graft function after liver transplantation, measured by aminotransferase and gamma glutamyl transferase activity, bilirubin, albumin and INR. | Two years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Individual need for immunosuppressive medication | measured by tacrolimus trough levels [ng/ml] and prednisolon dosage [mg/kgBW/day]. Tapering of tacrolimus and steroids will be performed according to a step-wise tapering protocol after day 180. | Two years | 
| Time to first biopsy-proven acute rejection (BPAR) | Protocol liver biopsy will be performed on day 180 post LT. Additional biopsies will be taken whenever clinically necessary. | Two years | 
| Immune monitoring: donor-specific antibodies (DSA) | [Participants with positive DSA] | Two years | 
| Patient and graft survival at 1 and 2 years after liver transplantation | [Death, Re-Transplantation] | up to Two years |