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

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