Adoptive Cord Blood Immunotherapy for EBV, CMV, BKV and Adenovirus Reactivation/Infection or Prophylaxis

This Phase I-II dose-finding trial to determine the optimal dose of intravenous (IV)
injection dose of donor-derived cytotoxic T lymphocytes (CTLs) specific for CMV, EBV, BKV and
Adenovirus. A maximum of 36 patients will be treated in up to 18 cohorts each of size 2, with
the first cohort treated at the lowest dose level 1, all successive doses chosen by the
EffTox method, and no untried dose level skipped when escalating.

The scientific goal of the trial is to determine an optimal IV-CTL cell dose level among the
three doses 1.0x107cells/m2, 2 x107cells/m2 and 5x107cells/m2., hereafter dose levels 1, 2,
3. Dose-finding will be done using the sequentially adaptive EffTox trade-off-based design of
Thall et al. To implement the design's model using the latest EffTox version 4.0.12 program,
doses will coded numerically to be 1, 2, 3.

CMV/AdV /EBV/BKV specific T cells will be thawed and given or thawed and diluted into a total
volume of 10 mL of Plasmalyte A by slow intravenous injection over 1-2 minutes. This is a
traditional Phase I dose escalation study of a single infusion of CMV/AdV/EBV/BKV-specific
CTLs to patients at risk for CMV and EBV reactivation and Adenoviral and BK virus infection
after umbilical cord blood transplantation. Three dose levels will be explored. The lowest
dose level will be 1x107cells/m2 and the highest will be 5x107/m2. There will be 2-6 patients
at each dose level (depending on toxicity) following the scheme below. The decision on
whether it is safe to escalate to next dose level or not will be made after at least two
patients in each dose level have finished their 45-days toxicity follow up. If the first two
patients have not finished their 45 days follow-up, up to 2 additional incoming patients can
be enrolled at the current dose level. In addition, we will give the option of administering
2 additional doses (at the same dose level), 28 days after the first infusion of the same
dose, in subjects who have a partial response after one dose or who have received other
therapy that may affect the persistence or function of the infused CTL in vivo. If there are
no toxicities and immunological efficacy is not seen at any dose, then the doses will be
further escalated after additional local and federal approval.

Dose Levels and Dosing Schedule

Dose Level CTL Dose Given from Day +30 post SCT

1. 1x107/m2

2. 2.0x107/m2

3. 5x107/m2

Escalation of Multi-virus-specific CTL infusions

CMV/AdV/EBV/BKV CTL will be given from day +30 either as prophylaxis or treatment for CMV,
EBV, BK and/or adenovirus infection. If the patient has viral reactivation or evidence of
CMV/EBV/AdV/BKV disease (e.g. pneumonitis, gastroenteritis and/or retinitis or Post
Transplant Lymphoproliferative Disorder (PTLD) or hemorrhagic cystitis the CTL can be given
with concurrent antiviral pharmacotherapy.

A dose escalation scheme utilizing cohorts of two patients will be used

At each dose level, two to six patients will be treated and observed for 45 days for
toxicity, dose escalation and for GvHD. If one of the initial cohort of two patients
experience Dose Limiting Toxicity (DLT), then four additional patients will be treated at
this dose level. If two or more the six patients experience DLT, then this dose level will be
considered unacceptable toxicity and the number of infused CTL will be de-escalated unless we
are at the initial dosing levels. If 1x107CTL/m2 results in unacceptable toxicity, the study
will be closed to accrual.

The MTD of infused CMV/AdV/EBV/BKV-specific CTL

The MTD of infused CMV/AdV/EBV-specific CTL will be that number at which DLT is observed in
at most one of six patients and the next higher dose presents unacceptably toxic, as defined
above. If the highest number of CTL safely infused is 5x107/m2 per dose, then no MTD exists
among these dosing levels. Note: at least six patients must be treated at the 5x107/m2 dose
level.

Inclusion Criteria:

Inclusion Criteria at the Time of Procurement

- Pediatric and adult patients (there are no lower and upper age limits for patients)
with malignant or nonmalignant diseases who are candidates for transplant.

- Patients must have a CB unit (or units) matched with the patient at 4, 5, or 6/6 HLA
class I (serological) and II (molecular) antigens. The unit selected for CTL expansion
must be either:

1. be cryopreserved in two fractions, with a minimum of 2.5x107 total nucleated
cells (TNC) 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. OR

2. be cryopreserved with a cell dose that totals > 3x10e7 TNC per kg pre thaw. On
thaw, 20% of the total volume will be used for CTL manufacture to give at day 30
or beyond and the remaining 80% will be used for the primary transplant.

3. For recipients of double CBT, if possible both CB units should be cryopreserved
in two fractions and T-cells will be made from both units if possible.

Inclusion Criteria at the Time of CTL Infusion

- Recipients of at least one unmanipulated cord blood unit as described above (i.e. from
a HLA matched or mismatched unrelated donor) transplant at risk for or with
CMV/Adenoviral/BKV and/or EBV infection or reactivation.

- Lansky/Karnofsky scores ≥60

- Absolute neutrophil count (ANC) greater than 500/u

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

- Life expectancy > 30 days

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

- Absence of severe hepatic disease. Direct bilirubin must be < 3 mg/dl and AST < 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 prednisone or equivalent

- Patients with Grade 3 hyperbilirubinemia

- Patients with other uncontrolled infections (except CMV and/or adenovirus and/or
EBVemia and/or BK viruria/viremia). 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

- Patients who have received investigational (IND) product within 28 days of screening
for CTL infusion under this study