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

Alberto Sánchez-Fueyo, Gavin Whitehouse, Nathali Grageda, Matthew E. Cramp, Tiong Y. Lim, Marco Romano, Sarah Thirkell, Katie Lowe, Laura Fry, Julie Heward, Alex Kerr, Jakia Ali, Chris Fisher, Gillian Lewis, Andrew Hope, Elisavet Kodela, Mike Lyne, Farzin Farzaneh, Shahram Kordasti, Irene Rebollo-MesaJuan Jose Lozano, Niloufar Safinia, Nigel Heaton, Robert Lechler, Marc Martínez-Llordella, Giovanna Lombardi

Research output: Contribution to journalArticlepeer-review

138 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)1125-1136
Number of pages12
JournalAmerican Journal of Transplantation
Volume20
Issue number4
DOIs
Publication statusPublished - Apr 2020
Externally publishedYes

Keywords

  • cellular transplantation (nonislet)
  • immunosuppression/immune modulation
  • liver transplantation/hepatology
  • T cell biology
  • tolerance
  • translational research/science

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