Flavio Vincenti | University of California | San Francisco, CA

Christian Larsen, MD | Emory University | Atlanta, GA

University of California | San Francisco, CA

Emory University | Atlanta, GA

The holy grail of transplantation is achieving successful transplantation without the requirement for maintenance immunosuppressive drugs and their long-term toxicities. Therefore strategies that produce long-term graft acceptance and induce donor specific tolerance (drug-free) or hyporesponsiveness (with minimal immunosuppression) can improve and prolong patient survival.

Recent understanding of the biology of rejection and tolerance has led to the development of novel therapies, in particular blockade of the costimulatory pathway. CTLA 4 Ig, a fusion receptor protein of CTLA 4 and the Fc portion of IgG and its second generation, LEA29Y, have been proven safe in patients with psoriasis and arthritis. LEA29Y is currently in a phase II trial in renal transplantation.

The goal of this proposal is to evaluate if the immunomodulatory effects of LEA29Y in a steroid and calcineurin inhibitors free regimen can facilitate drug minimization-withdrawal and induce tolerance to the allograft in select patients. Our hypothesis is that prolonged therapy with LEA29Y with avoidance of steroids and calcineurin inhibitors and the use of mechanistic and immune monitoring assays will result in a safe and effective drug minimization withdrawal strategy.

This regimen will utilize a five-dose course of daclizumab (first dose pre-op 2 mg/kg, followed by 4 additional doses of 1 mg/kg at 2 weekly intervals), LEA29Y given pre-op (10 mg/kg), at day 5 and every 2 weeks for 3 months and then monthly thereafter (dose reduced to 5 mg/kg at month 7). Patients will be treated with MMF for two weeks (1.5 g bid) and then discontinued and sirolimus 4 mg per day targeting a level of 10 ng/mL. At one year after transplantation patients who fulfill criteria for drug withdrawal (normal kidney allograft biopsy and quiescent immune monitoring profile) will gradually be withdrawn from sirolimus. At 2 years following transplantation, LEA29Y will be administered every 8 weeks in select patients (normal allograft biopsy and quiescent immune monitoring profile). At 3 years, patients will be offered the option of discontinuing LEA29Y if they fulfill the ITN drug withdrawal criteria including a normal allograft biopsy and quiescent immune monitoring profiles.