Abstract
Background aims
Thymic-derived regulatory T cells (tTreg) are critical regulators of the immune system.
Adoptive tTreg transfer is a curative therapy for murine models of autoimmunity, graft
rejection, and graft-versus-host disease (GVHD). We previously completed a “first-in-human”
clinical trial using in vitro expanded umbilical cord blood (UCB)-derived tTreg to prevent GVHD in patients undergoing
UCB hematopoietic stem cell transplantation (HSCT). tTreg were safe and demonstrated
clinical efficacy, but low yield prevented further dose escalation.
Methods
To optimize yield, we investigated the use of KT64/86 artificial antigen presenting
cells (aAPCs) to expand tTreg and incorporated a single re-stimulation after day 12
in expansion culture.
Results
aAPCs increased UCB tTreg expansion greater than eightfold over CD3/28 stimulation.
Re-stimulation with aAPCs increased UCB tTreg expansion an additional 20- to 30-fold.
Re-stimulated human UCB tTreg ameliorated GVHD disease in a xenogeneic model. Following
current Good Manufacturing Practice (cGMP) validation, a trial was conducted with
tTreg. tTreg doses up to >30-fold higher compared with that obtained with anti-CD3/28
mAb coated-bead expansion and Foxp3 expression was stable during in vitro expansion and following transfer to patients. Increased expansion did not result
in a senescent phenotype and GVHD was significantly reduced.
Discussion
Expansion culture with cGMP aAPCs and re-stimulation reproducibly generates sufficient
numbers of UCB tTreg that exceeds the numbers of T effector cells in an UCB graft.
The methodology supports future tTreg banking and is adaptable to tTreg expansion
from HSC sources. Furthermore, because human leukocyte antigen matching is not required,
allogeneic UCB tTreg may be a useful strategy for prevention of organ rejection and
autoimmune disease.
Key Words
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Article Info
Publication History
Published online: November 22, 2016
Accepted:
October 23,
2016
Received:
August 16,
2016
Identification
Copyright
© 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.
