Applicability, safety, and biological activity of regulatory T cell therapy in liver transplantation

Abstract

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 posttransplant. Circulating Tregs were isolated from blood or leukapheresis, expanded under good manufacturing practices (GMP) conditions, and administered intravenously 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 posttransplant. Thus, only 3 of the 17 patients who consented while awaiting liver transplantation were dosed. In contrast, all six patients who consented 6‐12 months posttransplant received the cell infusion. Treg transfer was safe, 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.

The Next Frontier of Regulatory T Cells: Promising Immunotherapy for Autoimmune Diseases and Organ Transplantations

“…A total of nine patients (three patients less than 6 months after transplantation and six patients more than 6 months post-transplantation) received the GMP-Treg cells. The study showed that Treg cell therapy was safe and increased the pool of circulating Treg cells (98).…”

Intrahepatic TH17/TReg Cells in Homeostasis and Disease—It’s All About the Balance

“…Adoptive T Reg transfer was protective in mice, and currently several clinical trials are testing the efficiency and safety in humans ( Romano et al, 2017 ). Another study tested the T Reg therapy in patients 6–12 months after liver transplantation and demonstrated an increase in circulating T Reg cells and reduced anti-donor T cell response ( Sanchez-Fueyo et al, 2020 ). Although the long-term effects are not evaluated, T Reg therapy could be a promising therapeutic approach.…”

Metabolic Optimisation of Regulatory T Cells in Transplantation

“…Mammalian transporter of rapamycin inhibition via rapamycin is a part of current immunosuppression protocols as well as ex vivo GMP Treg cell expansion protocols (1,19,20,111). This is because rapamycin improves Treg cell expansion, FOXP3 expression, and immunosuppressive function (25).…”

“…In this review, we discuss Treg cell metabolism and interlink it with their diverse functions. From a clinical perspective, the initial data from Phase I trials in transplant and non-transplant settings has shown Treg cells to be safe (1,(19)(20)(21)(22). The current Good Manufacturing Practice (GMP) protocols center on the hypothesis that the infusion of expanded autologous Treg cells could modulate the inflamed allograft microenvironment in favor of immunoregulation instead.…”