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

Everett Meyer

Status and phase: Terminated; Phase 2; Phase 1

Conditions: Acute Lymphoblastic Leukemia (ALL); Non-Hodgkin Lymphoma (NHL); Myelodysplastic Syndrome (MDS); Acute Myelogenous Leukemia (AML); Chronic Myelogenous Leukemia (CML); Leukemia, Acute; Chronic Lymphocytic Leukemia (CLL)

Treatments: Device: Fludarabine; Drug: Conventional T-cells; Drug: Regulatory T-cells; Drug: Thiotepa; Drug: CliniMACS CD34 Reagent System; Drug: Anti-thymocyte globulin, rabbit; Drug: Melphalan

Study type: Interventional

Funder types: Other

Identifiers

NCT01050764

IRB-15919

SU-03312009-2059 (Other Identifier)

BMT204 (Other Identifier)

Details and patient eligibility

About

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).

Full description

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.

Enrollment: 10 patients

Sex: All

Ages: Under 60 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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10 participants in 1 patient group

T-reg Cell Infusion after Allogeneic Stem Cell Transplant

Experimental group

Treatment:

Drug: Regulatory T-cells

Drug: Melphalan

Drug: Anti-thymocyte globulin, rabbit

Drug: Thiotepa

Drug: CliniMACS CD34 Reagent System

Drug: Conventional T-cells

Device: Fludarabine