Abstract
Incubation of umbilical cord blood (UCB) derived regulatory T-cells (Tregs) with fucosyltransferase enzyme improves their ability to home to the target tissue to prevent graft vs. host disease (GVHD). We report results of 5 patients (Double UCB Transplant, n=2; Peripheral Blood Matched Unrelated Donor Transplant, n=3) who received UCB-Tregs (Dose level = 1×106/kg), infused one day prior to the donor graft. All patients received their designated UCB-Treg dose without any infusion reaction. The ratio of conventional T-cells in donor graft was at least 10 times higher than infused UCB-Tregs (ratio range, 12-356). All patients engrafted at median of 13 days (range, 8-17 days). One patient died due to brain hemorrhage on day 45. A bi-modal increase of plasma IL-10 level occurred on day 7 and day 21 and notably, plasma IL-2 level dropped significantly in all patients at Day 7. All evaluable patients developed ≥grade II acute GVHD and at 1 year follow up, all were alive and without evidence of disease relapse. No increase in the chronic GVHD biomarkers (REG3a and Elafin) was observed at day 7. At the time of last follow up, all evaluable patients were off immune-suppression. Stage 2 of this clinical trial examining UCB-Treg at dose level= 1×107/kg is currently underway.
Highlights
We previously showed that 3rd party, ex-vivo expanded, umbilical cord blood (UCB) Treg cells can prevent graft versus host disease (GVHD) in xenogenic mouse model [1]
Five patients were treated at UCB Treg dose level: 1×106 cells/kg; 2 patients received non-fucosylated UCB Tregs followed by dUCB allogeneic stem cell transplant (AlloSCT) and 3 patients received fucosylated UCB Tregs followed by Peripheral Blood (PB) Matched Unrelated Donor Transplant (MUD) AlloSCT
We had to conduct the study with a low dose of UCB Tregs at 1×106 cells/kg when safety with higher dose www.oncotarget.com has been published by Brunstein et al [4, 5] due to the recommendation of MDACC safety board, since this was the first time UCB Treg cell product was manufactured at the MDACC GMP facility and the first time UCB underwent fucosylation for clinical use
Summary
We previously showed that 3rd party, ex-vivo expanded, umbilical cord blood (UCB) Treg cells can prevent graft versus host disease (GVHD) in xenogenic mouse model [1]. Efficacy of cultured UCB Tregs improves when incubated with fucosyltransferase-VI enzyme, which establishes Siayl-Lewis X moiety on P-selectin [2]. We hypothesized that adoptive therapy with fucosylated UCB Tregs would prevent GVHD and conducted a pilot clinical trial (https://www.clinicaltrials.gov NCT02423915). We report preliminary safety data in 5 patients undergoing allogeneic stem cell transplant (AlloSCT) (Double UCB Transplant (dUCBT)= 2; Peripheral Blood (PB) Matched Unrelated Donor Transplant (MUD) = 3) who received UCB Tregs at dose: 1×106 cells/kg (Fucosylated UCB Tregs = 3; Non-Fucosylated UCB Tregs = 2) that were matched at least at HLA 3/6 to recipient
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