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.
Highlights
Limited efforts to harness the therapeutic potential of Tregs in clinical solid organ transplantation (SOT), due to challenges with the isolation and expansion of Tregs for clinical use
Results available prior to release increase in the percentage of CD4+CD127−CD25+FOXP3+ Tregs generated in the recipient proliferating Peripheral blood mononuclear cells (PBMCs) when our Treg product was present compared to baseline (Fig. S4B)
Initial studies in stem cell transplantation pioneered the way for adoptive Treg cell therapy as an alternative to classic immune suppression
Summary
Limited efforts to harness the therapeutic potential of Tregs in clinical solid organ transplantation (SOT), due to challenges with the isolation and expansion of Tregs for clinical use. Using our unique expansion protocol and experience with personalized cellular therapies;[25] we enrolled nine living donor kidney transplant recipients into a three-tiered dose ranging study (0.5 × 109, 1.0 × 109, 5 × 109 Tregs / recipient). We subsequently monitored these patients post infusion and found maintained levels of Tregs throughout the study period. We report an in depth characterization of the nine Treg products infused into each recipient
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