Haploidentical Allogeneic Transplant With Post-transplant Infusion of Regulatory T-cells

A Feasibility Trial of Post-Transplant Infusion of Allogeneic Regulatory T Cells and Allogeneic Conventional T Cells in Patients With Hematologic Malignancies Undergoing Allogeneic Myeloablative Hematopoietic Cell Transplantation From Haploidentical-Related Donors

Patients with hematologic malignancies will receive myeloablative chemotherapy followed by stem cell rescue with bone marrow or hematopoietic peripheral blood stem cells collected by apheresis from a filgrastim- (G-CSF)-mobilized haploidentical related-donor, ie, hematopoietic peripheral blood stem cell transplant (HSCT).

This is dose-escalation study intended to evaluate the use of classification determinant 15-positive (CD15+), CD4+, CD127dim, and FoxP3+ regulatory T-cells (T-reg cells) supplemented by conventional T-cells (T-con cells), to enhance the efficacy of allogeneic (CliniMACS CD34+ selected) hematopoietic stem cell transplantation (allo-HSCT), in the setting of leukemia, lymphoma, and myelodysplastic syndrome (MDS). This study investigates amelioration of the impaired immune recovery and address the significant relapse incidence in the haploidentical HSCT setting.

Pre-transplant myeloablative conditioning will be melphalan; thiotepa; fludarabine and rabbit antithymocyte globulin (rATG).

Stem cell rescue will be with CD34+ selected cells. The rescue infusion will be supplemented with infusions of regulatory T-cells (T-reg) and conventional T-cells (T-con) from the same donor collection, on Treatment Days 14 and 16 respectively. CD34+ cell infusion day is Treatment Day 0.

T-reg cells are those cells enriched by immunomagnetic selection of CD25+ cells, and further purified by flow cytometric cell sorting for the CD15+, CD4+, CD127dim, FoxP3+ cell population. These cells are an enriched but naturally-occurring T-cell population.

T-con cells are unseparated/unfractionated cells, ie, as collected by the peripheral blood stem cells apheresis procedure.

Post-transplant follow-up is for 5 years.

Inclusion Criteria

RECIPIENT

• Histopathologically-confirmed:
• Acute leukemia (in first remission with poor risk factors and molecular prognosis)
• Acute myelogenous leukemia (AML) with -5,-7, t (6;9), tri8, -11
• Acute lymphoblastic leukemia (ALL) with Ph+ t (9;22), t (4;22), (q34;q11)
• Acute leukemia with refractory disease or > Complete Remission (CR) 1
• Chronic myelogenous leukemia (CML) (accelerated, blast or second chronic phase)
• Myelodysplastic syndrome (in high and high intermediate risk categories)
• Non-Hodgkin's lymphoma (NHL) with poor risk features and not suitable for autologous transplantation
• Refractory Chronic lymphocytic leukemia (CLL)
• At least 21 days from the end of most recent prior therapy to start of the transplant conditioning regimen
• Must be < 60 years old at time of registration.
• Karnofsky Performance Status (KPS) > 70%

Must have related donor who is:

• Genotypically human leukocyte antigen (HLA) -A, B,C and DR beta 1 (DRB1), DQ loci haploidentical to the recipient (but differing for 2 to 3 HLA alleles on the unshared haplotype in the graft-versus-host disease (GvHD) direction)
• No HLA-matched sibling or matched-unrelated donor is identified.
• Adequate cardiac and pulmonary function (left ventricular ejection fraction (LVEF) > 45%, diffusing capacity of the lungs for carbon monoxide (DLCO) >50% corrected for hemoglobin)
• Serum creatinine < 1.5 mg/dL OR Creatinine clearance > 50 mL/min for those above serum creatinine at least 1.5 mg/dL
• Serum bilirubin < 2.0 mg/dL
• Alanine transaminase (ALT) < 2x upper normal limit (ULN) (unless secondary to disease)
• No prior myeloablative therapy or hematopoietic cell transplantation

DONOR:

• Age ≤ 70 years
• Weight ≥ 25 kg.
• Medical history and physical examination confirm good health status as defined by institutional standards
• Seronegative for HIV Ag within 30 days of apheresis collection for:
• Hepatitis B surface antigen (sAg) or polymerase chain reaction (PCR) +
• Hepatitis C ab or PCR+
• Genotypically haploidentical as determined by HLA typing
• Female donors (child-bearing potential) must have a negative serum or urine beta-human chorionic gonadotropin (HCG) test within 3 weeks of mobilization
• Capable of undergoing leukapheresis
• Has adequate venous access
• Willing to undergo insertion of a central catheter if leukapheresis via peripheral vein is inadequate
• Capable of agreeing to second donation of peripheral blood progenitor cell (PBPC) (or a bone marrow harvest) should the patient fail to demonstrate sustained engraftment following the transplant
• Institutional review board (IRB)-approved consent form signed by donor or legal guardian > 18 years of age

Donor Selection in the priority order:

• Recipient's biological mother preferred, if available
• Other available haploidentical donors will be selected based upon the presence of natural killer (NK) alloreactivity between donor and recipient by high-resolution HLA typing of the C locus. An NK-alloreactive donor will be preferentially chosen. Recipients lacking a killer immunoglobulin-like receptor (KIR)-ligand present in the donor along with the corresponding KIR defines "NK alloreactivity".
• If more than one NK-alloreactive donor is available, preference is to cytomegalovirus (CMV)-seronegative donor

Exclusion Criteria

RECIPIENT:

• Suitable candidate for autologous transplantation or allogeneic transplantation with an available matched-related or matched-unrelated donor
• Seropositive for:
• HIV ab
• Hepatitis B sAg or PCR+
• Hepatitis C ab or PCR+
• History of invasive Aspergillosis
• Any active, uncontrolled bacterial, viral or fungal infection
• Uncontrolled central nervous system (CNS) disease involvement
• Lactating female

DONOR:

• Evidence of active infection or viral hepatitis
• Factors of increased risk for complications from leukapheresis or granulocyte-colony stimulating factor (G-CSF) therapy
• Lactating female
• HIV-positive