Applicability, Safety And Biological Activity Of Regulatory T Cell Therapy In Liver Transplantation

Regulatory T cells (Tregs) are a lymphocyte subset with intrinsic immunosuppressive properties that can be expanded in large numbers ex vivo and have been shown to prevent allograft rejection and promote tolerance in animal models. To investigate the safety, applicability and biological activity of autologous Treg adoptive transfer in humans, we conducted an open-label, dose escalation, Phase I clinical trial in liver transplantation. Patients were enrolled while awaiting liver transplantation or 6-12 months post-transplant. Circulating Tregs were isolated from blood or leukapheresis, expanded under GMP conditions, and administered i.v at either 0.5-1 million Tregs/kg or 3-4.5 million Tregs/kg. The primary endpoint was the rate of dose limiting toxicities occurring within 4 weeks of infusion. The applicability of the clinical protocol was poor unless patient recruitment was deferred until 6-12 months post-transplantation. Thus, only 3 out of the 17 patients consented while awaiting liver transplantation were dosed. In contrast, all 6 patients consented 6-12 months post-transplantation received the cell infusion. Treg transfer was safe and transiently increased the pool of circulating Tregs and reduced anti-donor T cell responses. Our study opens the door to employing Treg immunotherapy to facilitate the reduction or complete discontinuation of immunosuppression following liver transplantation.