Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall D1
Initial clinical trials have investigated the safety of regulatory T cells (Tregs) as a therapy during aberrant immune activation, like graft-versus-host disease (GVHD) following stem cell transplant, due to their ability to suppress alloimmune responses. There have been encouraging outcomes for Treg therapy which has led to the transition of Treg therapy into solid organ transplantation (SOT). In SOT the goal of Treg therapy would be to achieve a state or tolerance which will negate or lessen the reliance on lifelong immunosuppressive regimens. We have recently completed a phase I dose escalation clinical trial infusing billions of ex vivo expanded recipient polyclonal Tregs into living donor kidney recipients. We found all three doses (5 x 109, 1 x 109, and 0.5 x 109) were safe with no adverse infusion related side effects. Here we report an in depth analysis of our nine Treg infusion products. We achieved robust expansion and met all cell dose thresholds, despite variability in cause of end stage renal disease. Phenotypically, the Tregs expressed CD4+CD25+Foxp3+ throughout expansion, however, we did observe a decrease in Foxp3 expression from day 14 to day 21 of culture. Analysis of the Treg specific demethylation region within the Foxp3 promoter revealed high demethylation despite loss of Foxp3 expression. The expanded Treg product expressed increased CXCR3, CCR7, CXCR4, CD62L, and CD45RO compared to day 0, suggesting expansion improves homing to inflammation sites and secondary lymphoid tissues. We analyzed the unique T cell receptor (TCR) clones between each patients' apheresis and final Treg expanded product and found the top 10% clone frequency was decreased after Treg expansion, meaning our Treg product displayed a more diverse TCR repertoire than the apheresis product. Functional studies revealed greater than 50% suppression of the alloresponse in mixed lymphocyte reactions at a 1:32 (Treg: Responder) ratio which is highly suppressive. Interestingly, using a unique infectious tolerance in vitro assay we found our final Treg product caused a two fold increase in newly generated Tregs from recipient PBMCs compared to when no Tregs were present. These results will aid future Treg clinical trials as it closer defines and characterizes a safe Treg infusion product.
CITATION INFORMATION: Heinrichs J, Mathew J, Konieczna I, He J, Haung X, LeFever A, Leventhal J. In Depth Characterization of Ex Vivo Expanded Polyclonal Regulatory T Cells Used in a Phase I Clinical Trial Following Kidney Transplantation. Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:Heinrichs J, Mathew J, Konieczna I, He J, Haung X, LeFever A, Leventhal J. In Depth Characterization of Ex Vivo Expanded Polyclonal Regulatory T Cells Used in a Phase I Clinical Trial Following Kidney Transplantation. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/in-depth-characterization-of-ex-vivo-expanded-polyclonal-regulatory-t-cells-used-in-a-phase-i-clinical-trial-following-kidney-transplantation/. Accessed September 21, 2020.
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