Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics.
Acute graft-versus-host disease (aGVHD) is associated with high risk of morbidity and mortality and is a common complication after double umbilical cord blood (UCB) transplantation. To reduce these risks, we established a method of CD4(+)CD25(+)FoxP3(+) T regulatory cell (Treg) enrichment from cryopreserved UCB followed by a 18 (+) 1-day expansion culture including anti-CD3/anti-CD28 antibody-coated beads and recombinant human interleukin-2. In a "first-in-human" clinical trial, we evaluated the safety profile of UCB Treg in 23 patients. Patients received a dose of 0.1-30 × 10(5)UCB Treg/kg after double UCB transplantation. The targeted Treg dose was achieved in 74% of cultures, with all products being suppressive in vitro (median 86% suppression at a 1:4 ratio). No infusional toxicities were observed. After infusion, UCB Treg could be detected for 14 days, with the greatest proportion of circulating CD4(+)CD127(-)FoxP3(+) cells observed on day (+)2. Compared with identically treated 108 historical controls without Treg, there was a reduced incidence of grade II-IV aGVHD (43% vs 61%, P = .05) with no deleterious effect on risks of infection, relapse, or early mortality. These results set the stage for a definitive study of UCB Treg to determine its potency in preventing allogeneic aGVHD. This study is registered at http://www.clinicaltrials.gov as NCT00602693.
Brunstein
Claudio G
CG
Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN, USA. bruns072@umn.edu
Miller
Jeffrey S
JS
Cao
Qing
Q
McKenna
David H
DH
Hippen
Keli L
KL
Curtsinger
Julie
J
Defor
Todd
T
Levine
Bruce L
BL
June
Carl H
CH
Rubinstein
Pablo
P
McGlave
Philip B
PB
Blazar
Bruce R
BR
Wagner
John E
JE
D000328:Adult; D000368:Aged; D049109:Cell Proliferation; D002478:Cells, Cultured; D036101:Cord Blood Stem Cell Transplantation / Q000379:methods; D005260:Female; D005312:Fetal Blood / Q000166:cytology; D006086:Graft vs Host Disease / Q000276:immunology; D006801:Humans; D007938:Leukemia / Q000145:classification / Q000601:surgery; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology / Q000637:transplantation*; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult