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Clinical Trial
. 2016 Feb 25;127(8):1044-51.
doi: 10.1182/blood-2015-06-653667. Epub 2015 Nov 12.

Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect

Claudio G Brunstein  1 , Jeffrey S Miller  1 , David H McKenna  2 , Keli L Hippen  3 , Todd E DeFor  4 , Darin Sumstad  5 , Julie Curtsinger  3 , Michael R Verneris  3 , Margaret L MacMillan  3 , Bruce L Levine  6 , James L Riley  6 , Carl H June  6 , Chap Le  7 , Daniel J Weisdorf  1 , Philip B McGlave  1 , Bruce R Blazar  3 , John E Wagner  3
Affiliations
Clinical Trial

Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect

Claudio G Brunstein et al. Blood. .

Abstract

We studied the safety and clinical outcomes of patients treated with umbilical cord blood (UCB)-derived regulatory T cells (Tregs) that expanded in cultures stimulated with K562 cells modified to express the high-affinity Fc receptor (CD64) and CD86, the natural ligand of CD28 (KT64/86). Eleven patients were treated with Treg doses from 3-100 × 10(6) Treg/kg. The median proportion of CD4(+)FoxP3(+)CD127(-) in the infused product was 87% (range, 78%-95%), and we observed no dose-limiting infusional adverse events. Clinical outcomes were compared with contemporary controls (n = 22) who received the same conditioning regimen with sirolimus and mycophenolate mofetil immune suppression. The incidence of grade II-IV acute graft-versus-host disease (GVHD) at 100 days was 9% (95% confidence interval [CI], 0-25) vs 45% (95% CI, 24-67) in controls (P = .05). Chronic GVHD at 1 year was zero in Tregs and 14% in controls. Hematopoietic recovery and chimerism, cumulative density of infections, nonrelapse mortality, relapse, and disease-free survival were similar in the Treg recipients and controls. KT64/86-expanded UCB Tregs were safe and resulted in low risk of acute GVHD.

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Figures

Figure 1
Figure 1
(A) Logarithmic scale of the absolute number of nucleated cells after CD25+ immunomagnetic separation and at the end of the KT64/86-stimulated culture, of which the median proportion of CD4+CD25+ cells was 97% (range, 88-99) and with 87% (range, 78-95) expressing CD4+FoxP3+CD127–. (B) The median proportion, interquartile range, and range of CD4+FoxP3+CD127lowHelios+ cells that expressed the surface markers CD62L, OX40, and 41BB. (C) The median proportion, interquartile range, and range of chemokine receptors expression on CD4+FoxP3+CD127lowHelios+ cells; CXCR3+ (Th1-like), CXCR3–CCR6– (Th2-like), CXCR3–CCR4+CCR6+CCR10– (Th17-like), and CXCR3–CCR4+CCR6+CCR10+ (Th22-like). (D) The median proportion, interquartile range, and range of CD4+FoxP3+Helios+ cells that after ionophore and PMA stimulation expressed IFNγ, TNFα, IL-2, IL-4, IL-10, and IL-17. (E) The median proportion, interquartile range, and range of utilization of 24 v beta-chains in CD4+CD25++ cells from the Treg product. (F) The proportion of CD4+FoxP3+CD127low cells derived from the expansion product detected in the PB of the patients with an informative HLA marker (n = 7). The black lines on all panels represent the median values.
Figure 2
Figure 2
(A-C) Cumulative incidences of grade II-IV acute GVHD at day +100 (A), neutrophil recovery ≥500/μL by day +42 (B), and platelet recovery ≥20 000/μL at day +180 (C) for Treg recipients (solid line) and Siro/MMF controls (dotted line). (D) The density of infections at day +100 in Treg recipients (▪) and Siro/MMF controls (□).
Figure 3
Figure 3
(A-D) The absolute number of CD3+CD4+ (A) and CD4+CD45+CCR7+ (B) lymphocytes subsets at days +28, +60, +100, and +180 after transplantation for Treg recipients (gray square) and Siro/MMF controls (□). The cumulative incidence of NRM at 6 months (C) and the probability of disease-free survival at 1 year (D) for Treg recipients (solid line) and Siro/MMF controls (dotted line).
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