A Phase I Clinical Trial with Ex Vivo Expanded Recipient Regulatory T cells in Living Donor Kidney Transplants

Abstract

There is considerable interest in therapeutic transfer of regulatory T cells (Tregs) for controlling aberrant immune responses. Initial clinical trials have shown the safety of Tregs in hematopoietic stem cell transplant recipients and subjects with juvenile diabetes. Our hypothesis is that infusion(s) of Tregs may induce transplant tolerance thus avoiding long-term use of toxic immunosuppressive agents that cause increased morbidity/mortality. Towards testing our hypothesis, we conducted a phase I dose escalation safety trial infusing billions of ex vivo expanded recipient polyclonal Tregs into living donor kidney transplant recipients. Despite variability in recipient’s renal disease, our expansion protocol produced Tregs which met all release criteria, expressing >98% CD4+CD25+ with <1% CD8+ and CD19+ contamination. Our product displayed >80% FOXP3 expression with stable demethylation in the FOXP3 promoter. Functionally, expanded Tregs potently suppressed allogeneic responses and induced the generation of new Tregs in the recipient’s allo-responders in vitro. Within recipients, expanded Tregs amplified circulating Treg levels in a sustained manner. Clinically, all doses of Treg therapy tested were safe with no adverse infusion related side effects, infections or rejection events up to two years post-transplant. This study provides the necessary safety data to advance Treg cell therapy to phase II efficacy trials.

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

“…Clinical studies have demonstrated the safety of Treg adoptive transfer in graft‐versus‐host disease and type 1 diabetes mellitus . Furthermore, a number of trials have been initiated both in kidney and in liver transplantation . Liver transplantation constitutes an appealing clinical setting to evaluate the effects of Treg transfer given the lower immunogenicity of liver allografts and the substantial clinical experience that has been derived from trials of complete immunosuppression discontinuation .…”

Future prospects for CD8+ regulatory T cells in immune tolerance

“…Eight-Treg, supported by the ReSHAPE consortium, and that will take place in 2021 2 (https ://www.resha pe-h2020.eu/) (Figure 2 145 This rational strategy will be applied to the Eight-Treg clinical trial.…”

The emerging role of regulatory T cells following lung transplantation

“…148,149 However, Tregs have the potential to immunosuppress recipients and make them prone to infections and malignancy. 148,149 However, Tregs have the potential to immunosuppress recipients and make them prone to infections and malignancy.…”

“…148,149 However, Tregs have the potential to immunosuppress recipients and make them prone to infections and malignancy. 149 At this time, we do not understand if the efficacy seen in preclinical models of lung transplantation is due to antigen-specific immunosuppression or, instead, general suppression of inflammation within the graft microenvironment. Fortunately, methods have already been devised that manufacture clinical grade alloantigen-specific Tregs, such as the darTregs discussed above.…”