Ex-vivo Expanded Donor Regulatory T Cells for Prevention of Acute Graft-Versus-Host Disease

To evaluate the safety of sirolimus based immune suppression and ex-vivo expanded donor
regulatory T cells for the prevention of acute graft-versus-host disease following allogeneic
hematopoietic cell transplantation.

Inclusion Criteria:

- Signed informed consent

- Diagnoses:

a. Hematologic malignancies - Acute myelogenous leukemia (AML), acute lymphoblastic
leukemia (ALL), myelodysplastic syndrome (MDS), chronic lymphocytic leukemia (CLL),
non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), multiple myeloma (MM) - in complete
remission (CR). Complete remission is defined per morphologic, cytogenetic, FISH,
molecular, and radiographic imaging studies appropriate for each condition listed.

- AML, ALL: Normal values for absolute neutrophil count (>1000/microL) and platelet
count (>100,000/microL); Absence of extramedullary leukemia; Less than 5 percent
blast cells present in the bone marrow

- MDS: Bone marrow with ≤5 percent myeloblasts with normal maturation of all cell
lines; Peripheral blood demonstrates hemoglobin ≥11 g/dL, platelets ≥100 x
10^9/L, neutrophils ≥1 x 10^9/L, and no circulating blasts

- CLL: Absence of constitutional symptoms attributable to CLL; No lymph nodes >1.5
cm in diameter on computed tomography; No hepatomegaly or splenomegaly by
computed tomography; Absolute neutrophil count >1500/microL; Platelet count
>100,000/microL; No clonal lymphocytes in the peripheral blood by
immunophenotyping; Bone marrow with no evidence of clonal CLL (by flow cytometry
and/or immunohistochemistry

- NHL: No clinical evidence of disease or disease-related symptoms; Typically
FDG-avid lymphomas: a post-treatment residual mass of any size is permitted as
long as it is PET negative; Variably FDG-avid lymphoma/FDG avidity unknown: all
lymph nodes normal size by CT; Spleen and liver non-palpable and without nodules;
If pretreatment bone marrow biopsy was positive, repeat bone marrow biopsy must
be negative; if morphologically indeterminate, immunohistochemistry should be
negative If pretreatment bone marrow biopsy was positive, repeat bone marrow
biopsy must be negative; if morphologically indeterminate, immunohistochemistry
should be negative

- HL: No clinical evidence of disease or disease-related symptoms; A post-treatment
residual mass of any size is permitted as long as it is PET negative; Spleen and
liver must be non-palpable and without nodules; If a pre-treatment bone marrow
biopsy was positive, an adequate bone marrow biopsy from the same site must be
cleared of infiltrate; if this is indeterminate by morphology,
immunohistochemistry should be negative

- MM: Absence of monoclonal protein in serum and urine by immunofixation with no
current evidence of soft tissue plasmacytoma; Bone marrow aspirate and biopsy
must demonstrate less than 5 percent clonal plasma cells; In patients who lack
measurable M proteins in the serum and urine being monitored using the FLC
levels, the definition of CR requires a normalization of the free light chain
(FLC) ratio in addition to the above criteria

- MDS: May have achieved CR through either hypomethylating agent therapy, induction
chemotherapy, or other therapy

- MDS: Low/intermediate-1 IPSS risk category patients are eligible only if they
have failed prior therapy or are transfusion-dependent

- Peripheral blood white blood count (WBC) greater than 2,000 per microliter (required
for collection of dendritic cell precursors)

- Adequate vital organ function: Left ventricular ejection fraction (LVEF) ≥ 45% by
multigated acquisition (MUGA) scan or echocardiogram; Forced expiratory volume in one
second (FEV1), forced vital capacity (FVC), and diffusing lung capacity oxygenation
(DLCO) ≥ 50% of predicted values on pulmonary function tests; Transaminases (AST, ALT)
< 3 times upper limit of normal values; Creatinine clearance ≥ 50cc/min

- Infectious disease criteria:

- No active infection; infection controlled with antimicrobial therapy is not
excluded

- HIV negative by ELISA or reverse transcription polymerase chain reaction (RT-PCR)
[if ELISA is positive and RT-PCR is negative, the ELISA is considered false
positive]

- Hepatitis B and C negative by serology or RT-PCR

- Must complete full screening panel: HIV 1, 2 serology and RT-PCR; human T cell
lymphotropic virus types 1/2 (HTLV-1/2) serology; rapid plasma reagin (RPR)
serology; Epstein-Barr virus (EBV) serology; Cytomegalovirus (CMV) serology;
herpes simplex virus (HSV) serology; Varicella-. Zoster Virus (VZV) serology

- Performance status: Karnofsky Performance Status Score ≥ 60%.

- Agreement to utilize effective contraceptive methods during the study (for one year)

- Eligible donors will include siblings age ≥ 18 matched with the recipient at HLA-A, B,
C, and DRB1

Exclusion Criteria:

- Antithymocyte globulin (ATG) as part of the conditioning regimen