Successful expansion of functional and stable regulatory T cells for immunotherapy in liver transplantation

TY - JOUR

T1 - Successful expansion of functional and stable regulatory T cells for immunotherapy in liver transplantation

AU - Safinia, Niloufar

AU - Vaikunthanathan, Trishan

AU - Fraser, Henrieta

AU - Thirkell, Sarah

AU - Lowe, Katie

AU - Blackmore, Laura

AU - Whitehouse, Gavin

AU - Martinez-Llordella, Marc

AU - Jassem, Wayel

AU - Sanchez-Fueyo, Alberto

AU - Lechler, Robert I

AU - Lombardi, Giovanna

PY - 2016/1/17

Y1 - 2016/1/17

N2 - Strategies to prevent organ transplant rejection whilst minimizing long-term immunosuppression are currently under intense investigation with regulatory T cells (Tregs) nearing clinical application. The clinical trial, ThRIL, recently commenced at King's College London, proposes to use Treg cell therapy to induce tolerance in liver transplant recipients, the success of which has the potential to revolutionize the management of these patients and enable a future of drug-free transplants. This is the first report of the manufacture of clinical grade Tregs from prospective liver transplant recipients via a CliniMACS-based GMP isolation technique and expanded using anti-CD3/CD28 beads, IL-2 and rapamycin. We report the enrichment of a pure, stable population of Tregs (>95% CD4(+)CD25(+)FOXP3(+)), reaching adequate numbers for their clinical application. Our protocol proved successful in, influencing the expansion of superior functional Tregs, as compared to freshly isolated cells, whilst also preventing their conversion to Th17 cells under pro-inflammatory conditions. We conclude with the manufacture of the final Treg product in the clinical research facility (CRF), a prerequisite for the clinical application of these cells. The data presented in this manuscript together with the much-anticipated clinical results from ThRIL, will undoubtedly inform the improved management of the liver transplant recipient.

AB - Strategies to prevent organ transplant rejection whilst minimizing long-term immunosuppression are currently under intense investigation with regulatory T cells (Tregs) nearing clinical application. The clinical trial, ThRIL, recently commenced at King's College London, proposes to use Treg cell therapy to induce tolerance in liver transplant recipients, the success of which has the potential to revolutionize the management of these patients and enable a future of drug-free transplants. This is the first report of the manufacture of clinical grade Tregs from prospective liver transplant recipients via a CliniMACS-based GMP isolation technique and expanded using anti-CD3/CD28 beads, IL-2 and rapamycin. We report the enrichment of a pure, stable population of Tregs (>95% CD4(+)CD25(+)FOXP3(+)), reaching adequate numbers for their clinical application. Our protocol proved successful in, influencing the expansion of superior functional Tregs, as compared to freshly isolated cells, whilst also preventing their conversion to Th17 cells under pro-inflammatory conditions. We conclude with the manufacture of the final Treg product in the clinical research facility (CRF), a prerequisite for the clinical application of these cells. The data presented in this manuscript together with the much-anticipated clinical results from ThRIL, will undoubtedly inform the improved management of the liver transplant recipient.

U2 - 10.18632/oncotarget.6927

DO - 10.18632/oncotarget.6927

M3 - Article

C2 - 26788992

SN - 1949-2553

VL - 7

SP - 7563

EP - 7577

JO - Oncotarget

JF - Oncotarget

IS - 7

ER -