Study of Matched Unrelated Donor T Cell Infusion for Hematologic Malignancies After Allo-HSCT

Un-manipulated donor lymphocyte infusion (DLI) is used after stem cell transplantation to
treat and prevent relapse, to prevent infections and to establish full donor chimerism. The
addition of mature T cells which exhibit a broad repertoire of T cell immunity against viral
antigens, as well as against cancer antigens, might provide a clinical benefit. However, an
expected side effect of the presence of mature T cells is the potential occurrence of acute
graft-versus-host disease (aGvHD). The use of a suicide gene switch which would trigger the
initiation of the apoptosis of the alloreactive T cells by the infusion of a drug would
represent the potential optimal strategy for restoring early immunity with a built in "safety
switch" against GvHD side effects. Evidence has emerged that low-dose DLI followed by dose
escalation can achieve higher clinical response rate with lower GvHD occurrence. Optimization
of DLI dose and schedule as well as strategies of donor T-cell manipulation may lead to the
consistent ability to separate GvHD from graft-versus-tumor (GvT) activity and improve the
safety of DLI treatment. Our strategy is to infuse escalating doses of manipulated T cells
(from the same donor who provided the original hematopoietic stem cell graft) in adults and
children with recurrent or minimal residual disease (MRD) hematologic malignancies
post-allogeneic transplant to accelerate immune reconstitution thus improving graft versus
leukemic effect while reducing the severity of GvHD.

Inclusion Criteria:

- Subjects aged ≥ 18 yrs and ≤ 65 yrs;

- Clinical diagnosis of one of the following hematological malignancies:

- Leukemia

- Myelodysplastic Syndromes

- Lymphomas

- Multiple Myeloma

- Other high-risk hematological malignancy eligible for stem cell transplantation
per institutional standard;

- Recurrent disease that presents ≥100 days after, or minimal residual disease (MRD)
that presents ≥ 30 days following a hematopoietic stem cell transplant (HSCT) using a
matched unrelated donor located through the National Marrow Donor Program (NMDP);

- Life expectancy >10 weeks;

- Signed donor and patient/guardian informed consent;

- A 8/8 genotypic identical match as determined by high resolution typing for the
following genetic loci: human leukocyte antigen (HLA)-A, HLA-B, HLA-C and HLA-DRB1;

- Performance status: Karnofsky score > 50%;

- Subjects with adequate organ function as measured by:

- Bone marrow:

- > 25% donor T-cell chimerism post-transplant

- Absolute neutrophil count (ANC) >1 x 109/L

- Cardiac: left ventricular ejection fraction (LVEF) at rest ≥ 45%

- Pulmonary: forced expiratory volume (FEV) 1, forced vital capacity (FVC),
diffusion capacity of lunch for carbon monoxide (DLCO) ≥ 50% predicted (corrected
for hemoglobin)

- Hepatic: direct bilirubin ≤ 3x upper limit of normal (ULN), or aspartate
aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 5x ULN

- Renal: creatinine ≤ 2x of ULN for age.

Exclusion Criteria:

- ≥ Grade II acute GVHD or chronic extensive GVHD due to a previous allograft at the
time of screening;

- Active central nervous system (CNS) involvement with malignant cells (≤ 2 months prior
to consenting);

- Current uncontrolled bacterial, viral or fungal infection (currently taking medication
with evidence of progression of clinical symptoms or radiologic findings); the
principal investigator is the final arbiter of this criterion;

- Positive HIV serology or viral RNA;

- Pregnancy (positive serum β human chorionic gonadotropin [HCG] test) or
breast-feeding;

- Fertile men or women unwilling to use effective forms of birth control or abstinence
for one year after transplantation;

- Bovine product allergy.