Safety, Toxicity and MTD of One Intravenous IV Injection of Donor CTLs Specific for CMV and Adenovirus

We plan to grow T cells from the cord blood in the laboratory in a special way, to see if
they can help prevent or treat infections in transplant patients with these viruses. This
therapy with specially trained T cells (called CTLs) has had activity against these viruses
when the cells are made from donor blood and given to patients receiving bone marrow or
blood stem cell transplants. We want to find out if we can use CTLs that we will make from
cord blood to prevent or treat viral infections when the patient's immunity is weak after
receiving the cord blood transplant. These cells are called "CMV/AdV specific CTLs" because
they can attack those two viruses.

The doctor will already have found a cord blood unit that is suitable for the patient's
transplant. If the patient agrees to this study we will take 5-10 ml (1-2 teaspoons) from
this cord blood unit before the transplant. We will only take as much cord blood as is
available in a specially frozen small fraction of the cord blood unit.

We will use this cord blood to grow T cells in the lab. From this blood we will first grow
special type of cells called dendritic cells and we will put a specially produced human
virus (adenovirus) that carries the CMVpp65 gene into these dendritic cells. The dendritic
cells will be irradiated so they cannot grow and then used to stimulate the T cells. This
stimulation will train the T cells to kill cells with CMV and adenovirus on their surface.

We will then grow large numbers of these AdV/CMV-specific CTLs by more stimulation with EBV
infected B cells (which we will make from the cord blood by infecting them with EBV in the
laboratory). We will also put the special virus into these B cells so that they too have
AdV/CMV. Again, these B cells will be treated with radiation so they cannot grow. Once we
have made enough T cells we will test them to make sure they kill cells infected with
Adenovirus and CMV. To make sure that these cells won't attack the patient's own healthy
tissues, we test these cells against some of the blood cells that we will grow in the
laboratory. These will be used to check to see if the AdV/CMV CTL can attack them.
Alternatively, we may take blood from a first degree relative or take a small piece of skin
from the patient to grow skin cells, which can also to be used to check if AdV/CMV CTL can
attack them. The skin biopsy can be done at the same time as another procedure such as a
bone marrow biopsy.

The cord donor's AdV/CMV CTL cells will be thawed and injected into the IV line over a
period of up to 10 minutes.Patients may be premedicated with Benadryl and Tylenol. If the
patient agrees and if he/she is well enough, one dose of CTL will be given on or after day
30 following transplant. If the patient does not have AdV/CMV infection we will not give
antiviral medications to them during this study but we will monitor the patient closely to
check for AdV/CMV infection. If the patient does have AdV/CMV infection before CTL infusion
they may also be treated with antiviral medications during this study. We will monitor the
patients closely for AdV/CMV infection by collecting blood and possibly urine and stool and
testing them for AdV/CMV.

INCLUSION CRITERIA:

Inclusion criteria at the time of Procurement:

- Patient with malignant or nonmalignant diseases who are candidates for transplant.

- Patients must have a single CB unit matched with the patient at 4, 5, or 6/6 HLA
class I (serological) and II (molecular) antigens. The unit must be cryopreserved in
two fractions, with a minimum of 2.5x10^7 total nucleated cells per kg pre-thaw in
the fraction which will be used for the primary transplant. The remaining fraction
will be used to generate the CTLs to give at day 30 or beyond as described below.

Inclusion criteria at the time of CTL infusion:

- Recipients of a single cord blood unit fractionated into 2 fractions (i.e. from a HLA
matched or mismatched unrelated donor) transplant at risk for or with CMV/Adenoviral
disease or reactivation.

- Lansky/Karnofsky scores 60 or greater

- Absolute neutrophil count (ANC) greater than 500/ul.

- No evidence of GVHD > Grade II at time of enrollment.

- Life expectancy > 30 days

- Absence of severe renal disease (Creatinine > x 3 normal for age)

- Absence of severe hepatic disease. Direct bilirubin must be less than 3 mg/dl and AST
less than 5x upper limit of normal

- Patient must be at least 30 days post transplant to be eligible to receive CTL

- Written informed consent and/or signed assent line from patient, parent or guardian.

- Patient not on Fi02 of >60%

EXCLUSION CRITERIA:

Exclusion criteria at the time of Procurement:

- Pregnant or Lactating

- Patients with active central nervous system disease

- Patients with Karnofsky performance status <70%

- Patients with grade 3 or 4 or primary myelofibrosis

- Patients with suitable related donors

Exclusion criteria at the time of CTL infusion:

- Pregnant or lactating

- Unable to wean steroids to 0.5 mg/kg/day or less prednisone.

- Patients with other uncontrolled infections (except CMV and/or adenovirus and/or
EBVemia in absence of PTLD). For bacterial infections, patients must be receiving
definitive therapy and have no signs of progressing infection for 72 hours prior to
enrollment. For fungal infections patients must be receiving definitive systemic
anti-fungal therapy and have no signs of progressing infection for 1 week prior to
enrollment. Progressing infection is defined as hemodynamic instability attributable
to sepsis or new symptoms, worsening physical signs or radiographic findings
attributable to infection. Persisting fever without other signs or symptoms will not
be interpreted as progressing infection.

- Patients with less than 50% donor chimerism in either peripheral blood or bone marrow
or patients with relapse of original disease.