Allogeneic Virus-Specific Cytotoxic T-Lymphocytes(CTL), Persistent/Recurrent Viral Infection Post-HSCT (EAP CHALLAH)

The CTL lines were made at Baylor College of Medicine from donors for other transplant
patients or other normal donors from the National Marrow Donor Program. All donors were
screened in the same way as blood donors. When the CTL lines were made, blood was taken from
the donors and used to grow T cells. To do this, we first infected a type of blood cells
called monocytes with a specially produced adenovirus gene that also carries part of the CMV
gene. The monocytes with these new genes then stimulated the T cells. This stimulation
trained the T cells to kill cells with this part of the CMV virus or with adenovirus.

We then grew these CTLs with more stimulation with EBV infected cells (which we made from
donor blood by infecting them with EBV in the laboratory). We also put the adenovirus that
carries the CMV gene into these EBV infected cells so that they too had CMV and adenovirus
proteins. These EBV infected cells were treated with radiation so they cannot grow. By this
type of culture, we grew out T cells that can see and attack cells infected with EBV,
adenovirus or CMV. Once we made sufficient numbers of T cells we tested them to make sure
they killed cells infected with these viruses and then froze them.

The cells will be thawed and injected into an intravenous line over 1-5 minutes.

All participants on this study will get the same dose of cells. However if the subject's
infection responds to the CTLs, s/he may be offered up to 4 more doses at two-week
intervals. If the infection does not respond, the doctors may also try a line from a
different donor.

Inclusion Criteria:

1. Prior myeloablative or non-myeloablative allogeneic hematopoietic stem cell
transplant using either bone marrow, peripheral blood stem cells or single or double
umbilical cord blood.

2. CMV, adenovirus or EBV infection persistent despite standard therapy

1. For CMV infection

- Patients with CMV disease: defined as the demonstration of CMV by biopsy
specimen from visceral sites (by culture or histology) or the detection of
CMV by culture or direct fluorescent antibody stain in bronchoalveolar
lavage fluid in the presence of new or changing pulmonary infiltrates OR

- Failure of antiviral therapy: defined as the continued presence of pp65
antigenemia (>1+ cell/100,000 cells) or DNAemia (as defined by reference
lab performing PCR assay but usually >400 copies/ml) after at least 7 days
of antiviral therapy OR

- Relapse after antiviral therapy defined as recurrence of either pp65
antigenemia or DNAemia after at least 2 weeks of antiviral therapy

- For CMV infection, standard therapy is defined as 7 days therapy with
Ganciclovir, Foscarnet or Cidofovir for patients with disease or recurrence
after 14 days therapy

2. For EBV infection

- EBV infection is defined as:

- Biopsy proven lymphoma with EBV genomes detected in tumor cells by
immunocytochemistry or in situ PCR OR

- Or clinical or imaging findings consistent with EBV lymphoma and
elevated EBV viral load in peripheral blood.

- For EBV infection, standard therapy is defined as rituximab given at
375mg/m2 in patients for 1-4 doses with a CD20+ve tumor

- Failure is defined as

- There was an increase or less than 50% response at sites of disease
for EBV lymphoma OR

- There was a rise or a fall of less than 50% in EBV viral load in
peripheral blood or any site of disease

3. For adenovirus infection or disease

- Adenovirus infection is defined as the presence of adenoviral positivity as
detected by PCR, DAA or culture from ONE site such as stool or blood or
urine or nasopharynx OR

- Adenovirus disease will be defined as the presence of adenoviral positivity
as detected by culture from two or more sites such as stool or blood or
urine or nasopharynx

- Standard therapy is defined as 7 days therapy with Cidofovir (if renal
function permits this agent to be given).

- Failure is defined as a rise or a fall of less than 50% in viral load in
peripheral blood or any site of disease as measured by PCR or any other
quantitative assay).

3. Patients with multiple CMV, EBV or Adenovirus infections are eligible given that each
infection is persistent despite standard therapy as defined above. Patients with
multiple infections with one persistent infection and one controlled infection are
eligible to enroll.

4. Clinical status at enrollment to allow tapering of steroids to less than 0.5
mg/kg/day prednisone.

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

Exclusion Criteria:

1. Received ATG, or Campath or other immunosuppressive T cell monoclonal antibodies
within 28 days of screening for enrollment.

2. Uncontrolled infections. 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.

3. 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.

4. Received donor lymphocyte infusion (DLI) within 28 days.

5. Active acute GVHD grades II-IV.

6. Active and uncontrolled relapse of malignancy

7. Pregnant or lactating in female patients, if applicable (childbearing potential who
have received a reduced intensity conditioning regimen).