Mesenchymal Stem Cells Under Basiliximab/Low Dose RATG to Induce Renal Transplant Tolerance

Summary

This a pilot, explorative study to define the safety and biological/mechanistic effect of the systemic intravenous infusion of syngeneic ex-vivo expanded MSCs in living-related kidney transplant recipients (one or two HLA haplotype mismatches) under basiliximab/low-dose RATG induction therapy and maintenance immunosuppressive drugs with the ultimate objective to test the feasibility of safely achieving graft tolerance in a subsequent efficacy pilot study.

Specific objectives To compare changes in the immunophenotype and ex-vivo T-cell functional tests from samples of peripheral blood and measurement in the urine of messenger RNA for FoxP3,in kidney transplant recipients given or not syngeneic (from the recipient) MSC infusion under basiliximab/low-dose RATG induction therapy and maintenance immunosuppressive treatment with low-dose cyclosporine (CsA) plus low-dose mycophenolate mofetil (MMF).

This will assess at different time up to 12 months post transplant. In addition the safety profile of MSC infusion will be investigated. We have planned to start with the safety and biological/mechanistic study in 6 living-related kidney transplant recipients. Three patients will receive ex-vivo expanded syngeneic MSC infusion (2x106 MSCs per kilogram body weight) at the time of kidney transplant, and 3 additional patients no cells (controls), both under the cover of induction therapy with basiliximab and low-dose RATG, and maintenance immunosuppression with low-dose CsA and MMF. Randomization to MSC or no cell infusion will be performed at the time the recipient will sign the informed consent to participate to the study.

Should this biological/mechanistic ex vivo studies document that MSC infusion allows the development of an immune microenvironment permissive to graft tolerance, a pilot efficacy study to achieve operational tolerance after complete withdrawal of maintenance immunosuppressive therapy will follow.

In this additional pilot explorative efficacy study all consecutive patients will be included and followed until the first episode of rejection (if any) will occur or 29 consecutive patients have successfully withdrawn the immunosuppressive therapy. This has been estimated according to the Simon's two-stage minimax design.

Conditions

• Kidney Transplant

Interventions

BIOLOGICAL

Mesenchymal stem cells infusion, Basiliximab,Methylprednisolone,RATG ,Cyclosporine ,Mycophenolate mofetil

Cell therapy Mesenchymal cells infusion. Induction therapy: Basiliximab (20 mg i.v.day 0 and day 4 post-tx). Low dose RATG (0.5 mg/kg/day i.v. day 0-6 post-tx). Methylprednisolone (500 mg to 25 mg from day 0 to 6 post-tx. Then stop). Maintenance therapy: Cyclosporine (from day 0: dose according to target trough blood level). Mycophenolate mofetil (750 mg b.i.d. from day 1 post-tx).

DRUG

Basiliximab, Methylprednisolone,RATG,Cyclosporine,Mycophenolate mofetil

Routine immunosuppressive therapy Induction therapy: Basiliximab (20 mg i.v.day 0 and day 4 post-tx). Low dose RATG (0.5 mg/kg/day i.v. day 0-6 post-tx). Methylprednisolone (500 mg to 25 mg from day 0 to 6 post-tx. Then stop). Maintenance therapy: Cyclosporine (from day 0: dose according to target trough blood level). Mycophenolate mofetil (750 mg b.i.d. from day 1 post-tx).

Sponsors & Collaborators

• Mario Negri Institute for Pharmacological Research

  lead OTHER

Principal Investigators

• Giuseppe Remuzzi, MD · Department of Immunology and Clinical Transplantation / Mario Negri Institute for Pharmacological Research and Ospedali Riuniti BG

• Norberto Perico, MD · Mario Negri Institute for Pharmacological Research, Ranica BG

• Marina Noris, CH Ph · Mario Negri Institute for Pharmacological Research, Ranica BG

• Martino Introna, MD · Cell and Gene therapy Laboratory "G. Lanzani" BG

• Alessandro Rambaldi, MD · Hematology Unit - Ospedali Riuniti BG

Study Design

Allocation

RANDOMIZED

Purpose

OTHER

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

80 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2008-05-31

Primary Completion

2013-07-31

Completion

2013-12-31

Countries

• Italy

Study Locations