RATIONALE: Giving chemotherapy, such as fludarabine and cyclophosphamide, and total-body irradiation before a donor umbilical cord blood transplant helps stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Giving an infusion of the donor's T-regulatory cells after the transplant may decrease this effect. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. However, the donor immune system may also react against the recipient's tissues (graft-versus-host disease). PURPOSE: This phase I trial is studying the side effects and best dose of donor T-regulatory cells after an umbilical cord blood transplant in treating patients with advanced hematologic cancer or other disorder.
OBJECTIVES: Primary * Determine the maximum tolerated dose (MTD) of umbilical cord blood (UCB)-derived T-regulatory (Treg) cells. Secondary * Estimate the proportion of patients with detectable circulating Treg cells at 0, 1, 3, 7, and 14 days after infusion. * Estimate the risk of grades II-IV and III-IV acute graft versus host disease (GVHD) at day +100 with the infusion of Treg cells. * Estimate the proportion of patients with sustained donor engraftment. * Estimate the proportion of patients with double chimerism at 6 months and 1 year. * Determine the speed and cumulative incidence of neutrophil recovery by day 42 and platelet recovery by 6 months after UCB transplantation. * Estimate the risk of chronic GVHD at 1 year. * Estimate the probability of disease-free survival at 100 days and 1 year. * Estimate the risk of fungal and viral infections at 1 year * Estimate the risk of relapse at 1 year * Characterize the pattern of immune cell recovery over 1 year OUTLINE: This is a dose-escalation study of umbilical cord blood (UCB)-derived T-regulatory (Treg) cells. Patients receive nonmyeloablative UCB transplantation and post-transplant immunosuppression as in protocol UMN-2005LS036 (without antithymocyte globulin during conditioning regimen). * Nonmyeloablative conditioning and UCB transplantation: Patients receive allopurinol on days -7 to day 0, fludarabine phosphate intravenously (IV) over 1 hour on days -6 to -2 and cyclophosphamide IV over 2 hours on day -6; undergo total-body irradiation (TBI) once on day -1; and undergo UCB transplantation on day 0. * Immunosuppression therapy: Beginning on day -3 and continuing until day +100, patients receive sirolimus intravenously (IV) with 8-12 mg oral loading dose followed by a single dose of 4mg/day with a target serum concentration of 3-12 mg/mL with a taper until day +180. Patients also receive mycophenolate mofetil IV or orally every 8 hours on days -3 to +30. * Radiation therapy: total body irradiation is administered on Day -1 of 200 cGy. * UCB Treg cell infusion: Patients receive escalating doses of UCB-derived CD4+ CD25+ Treg cells IV on day +1 (and Day +15 for dose level 5 only) until the maximum tolerated dose is obtained. After completion of study treatment, patients are followed at day 180, 360, and 720.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
41
Infusion of umbilical cord blood
Administration begins Day -7 through Day 0, tablet or powder prescribed on an individual basis.
40 mg/m\^2 intravenously over 1 hour on Days -6, -5, -4, -3, -2
50 mg/kg intravenous over 2 hours on Day -6
200 cGy on Day -1
Infusion of T regulatory cells on Day +1 (also Day +15 for Dose level 5 only). Dose escalation ranges include 1, 3, 10, 30, 100, 300 1000, and 300 x 10\^5 Treg/kg.
Beginning on day -3 and continuing until day +100, patients receive sirolimus intravenously (IV) with 8-12 mg oral loading dose followed by a single dose of 4mg/day with a target serum concentration of 3-12 mg/mL with a taper until day +180.
Masonic Cancer Center at University of Minnesota
Minneapolis, Minnesota, United States
Maximum tolerated dose
Nine dose levels of CD4+CD25+ Treg are scheduled with the doses being 1, 3, 10, 30, 30+30, 100, 300, 1000, and 3000 x 10\^5 Treg/kg recipient body weight. The dose escalation will proceed in cohorts of one patient until the first dose limiting toxicity (DLT) is observed.
Time frame: 48 Hours
Number of patients with detectable Treg cells
determined by polymerase chain reaction (PCR) and flow cytometry
Time frame: Days 0, +1, +3, +7, and +14 after Treg cell infusion
Number of Patients with grade II-IV and grade III-IV acute graft versus host disease (GVHD)
Patients will be assessed weekly for GVHD between days 0 and 100 after transplantation using standard criteria. Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea and maximum bilirubin level. Incidence of grades II-IV and grades III-IV GVHD by day 100 will be monitored.
Time frame: Day 100
Number of patients with sustained donor engraftment
Time frame: Day 100
Number of patients with double chimerism
Time frame: 6 Months and 1 Year
Incidence of neutrophil recovery after umbilical cord blood (UCB) transplantation
Time frame: Day 42
Number of Patients with Chronic Graft Versus Host Disease (GVHD)
Time frame: 1 Year
Number of Patients with disease-free survival
Time frame: Day 100 and 1 Year
Number of Patients with Fungal and Viral Infections
Count of reported infections.
Time frame: 1 Year
Incidence of platelet recovery after umbilical cord blood (UCB)
Time frame: 6 Months After Transplant
Number of Patients with Disease Relapse
Time frame: 1 Year
Percent of Patients with Immune Cell Recovery
Time frame: 1 Year
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