T-Regulatory Cell Infusion Post Umbilical Cord Blood Transplant in Patients With Advanced Hematologic Cancer

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.

Inclusion criteria

• Ages 18 to 75 years old
• Eligible for and co-enrolled on protocol UMN-2005LS036, for treatment of any of the following advanced hematologic malignancies:

• Acute leukemias in complete remission (high risk CR1 or subsequent CR); chronic myelogenous leukemia (except refractory blast crisis); myelodysplastic syndrome with severe pancytopenia or complex cytogenetics, large-cell lymphoma, Hodgkin's lymphoma and multiple myeloma, chronic lymphocytic leukemia/small lymphocytic lymphoma, marginal zone b-cell lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia may be eligible after initial therapy.
• Have three partially HLA matched umbilical cord blood (UCB) units (1-2 units for UCB transplantation per MT2005-02 and 1 unit for the Treg cell infusion.)
• Adequate organ function

Exclusion criteria

• Patients not exposed to highly immunosuppressive single agent or multi-agent chemotherapy within 3 months, or an ablative preparative regimen for autologous hematopoietic stem cell transplant (HCT) within 1 year.
• Pregnancy or breastfeeding
• Current active serious infection
• Evidence of human immunodeficiency virus (HIV) or known HIV positive serology
• Patients with acute leukemia in morphologic relapse/persistent disease defined as >5% blasts in a > or = 15% cellular bone marrow or any % blasts if blasts have unique morphologic markers (e.g., Auer rods) or associated cytogenetic markers that allows morphologic relapse to be distinguished are not eligible.
• Chronic myelogenous leukemia in refractory blast crisis.
• Active central nervous system malignancy.