This is a unique dose-escalation trial that will titrate doses of umbilical cord blood (UCB) Treg and CD3+ Teff cells with the goal of infusing as many CD3+ Teff cells as possible without conferring grade II-IV acute graft-versus-host disease (GVHD). In this study, the investigators propose to add UCB Treg and UCB CD3+ Teff cells to the two TCD UCB donor units with the goal of transplanting as many CD3+ Teff cells as possible without reintroducing risk of acute GVHD. The investigators hypothesize that Treg will permit the reintroduction of CD3+ Teff cells that will provide a bridge while awaiting HSC T cell recovery long term. The co-infusion of Treg will prevent GVHD without the need for prolonged pharmacologic immunosuppression.
Based on prior studies, the first patient will start at lowest dose combination (3 x 10\^6/kg of Treg and 3 x 10\^6/kg of CD3+ Teff cells). One patient will be entered at each level with a minimum of 35 days to observe the patient prior to moving to the next dose level. (1) If GVHD does not occur, a "successful step", then the CD3+ Teff cell dose will increase to the next higher level for the next patient; (2) If GVHD occurs, a "failed step", then Treg dose will increase to the next higher level for the next patient. It would take a minimum of 5 (if no GVHD) and maximum of 9 patients (if GVHD is observed at each level) to complete all Treg:CD3+ Teff cell combinations. An additional 10 patients will be enrolled to verify that this reflects the optimal combination and evaluate its safety profile.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Given by infusion on Day 0 after transplantation - Five doses of Treg (3 x 10\^6/kg, 10 x 10\^6/kg, 30 x 10\^6/kg, 100 x 10\^6/kg and 300 x 10\^6/kg)
Given by infusion on Day 0 after transplantation - 5 doses of CD3+ Teff cells (3 x 10\^6 cells/kg, 6 x 10\^6 cells/kg, 9 x 10\^6 cells/kg, 12 x 10\^6 cells/kg, and 15 x 10\^6 cells/kg with the latter dose representing the median number of CD3+ cells in two UCB unit grafts
Given intravenously on Days -8 through -6, 25 mg/m\^2 over 1 hour
Given intravenously on Day -7 and -6, 60 mg/kg
Given on Days -4 through -2, 165 cGY twice a day.
Infusion given on day 0
Masonic Cancer Center, University of Minnesota
Minneapolis, Minnesota, United States
Optimal Cell Dose Mixture
Determine the optimal cell dose mixture of UCB T regulatory and CD3+ T effector cells without the development of grade II-IV acute GVHD
Time frame: Day 0
Determine incidence of infusional toxicity
reaction that occurs with 48 hours of product infusion
Time frame: 48 hours
Incidence of neutrophil recovery
Determine the incidence of neutrophil recovery (absolute neutrophil count ≥ 500/uL) at day 42
Time frame: Day 42
Incidence of double and single chimerism
Determine incidence of double and single unit chimerism at various time points
Time frame: Day +21, Day +180, 1 Year
Incidence of Viral and Fungal Infections
Determine incidence of viral and fungal infections at 1 year
Time frame: 1 Year
1 Year Survival
Estimate the probability of survival at 1 year
Time frame: 1 Year
Incidence of Grade III-IV Acute Graft-Versus-Host Disease
Determine the incidence of grade III-IV acute GVHD at day 100
Time frame: Day 100
Incidence of Treatment Related Death
Determine the incidence of treatment related mortality (TRM) at 6 months
Time frame: 6 Months
Incidence of Platelet Recovery
Determine the incidence of platelet recovery (platelet count ≥ 50,000/uL) at 1 year
Time frame: 1 Year
Incidence of Chronic Graft-Versus-Host Disease
Determine the incidence of chronic GVHD at 1 year
Time frame: 1 Year
Incidence of Relapse
Determine the incidence of relapse at 1 year
Time frame: 1 Year
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