Multivirus-specific T Cells for the Treatment of Virus Infections After Stem Cell Transplant

These VST lines have been made at Baylor College of Medicine from donors for other transplant
patients or other normal donors some of whom were from the National Marrow Donor Program. All
donors have been screened with the standard blood bank donor questionnaire, medical history
and testing for infectious disease by a doctor who is experienced in screening transplant
donors. Only donors who have cleared this process and were deemed to be eligible provided
blood for VST generation.

The lines were made using a special process. To make the VSTs investigators mixed donor cells
with small pieces of proteins, called peptides that come from adenovirus, CMV, EBV, BKV and
HHV6. These peptides stimulate donor T cells that react against the viruses to grow and train
the donor T cells to kill cells that are infected with CMV, EBV, adenovirus, BKV and HHV6.

Once the investigators made sufficient numbers of VSTs, they tested them to make sure they
would target cells infected with these virusesbut not normal cells. Then the cells were
frozen.

For patients treated on this study, the VSTs will be thawed and injected into their
intravenous line. The patient will remain in the clinic for at least one hour after the
infusion. After the patient receives the cells, their transplant doctor will monitor the
levels of the virus the patient is infected with in their blood. The investigators will also
take blood to see how long the VSTs given to the patient last in their body.

The patient will continue to be followed by their doctors after the injection. The patient
will either be seen in the clinic or will be contacted by a research nurse to follow up for
this study every week for 6 weeks then at 3, 6 and 12 months. The patient may have other
visits for their standard care.

The patient will also have regular blood tests done to follow their counts and the viral
infection, but most of these will be done as part of their standard medical care. To learn
more about the way the VSTs are working in the patient's body, up to an extra 30-40 ml (6-8
teaspoons) of blood will be taken before the infusion and then at 1, 2, 3, 4, 6 weeks and 3
months. Blood should come from the central intravenous line, and should not require extra
needle sticks.

All participants on this study will be infused with the same number (dose) of cells. If after
the first treatment the patient has a persistent infection, we would discuss this with
him/her and allow an option to receive more treatments. These additional treatments might be
with cells from the same donor or if we feel that there is another donor's whose cells might
be better for the patient, we would use cells from a different donor. This second product
will be administered at the same dose level 28 days after the initial infusion, and
subsequent infusions should be at least 14 days apart. After each VST infusion, the patient
will be monitored as described above.

Inclusion Criteria:

For Initial VSTs and subsequent infusions: patients will be eligible following any type of
allogeneic transplant if they have CMV, adenovirus, EBV, BK virus and/or HHV6
infection/disease persistent or recurrent despite 14 days of standard therapy OR after
failure of treatment after 7 days of standard therapy OR if unable to tolerate standard
therapy. Patients with persistent JC virus infection will be eligible as well.

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

2. Treatment of the following persistent or relapsed infections despite standard therapy;

1. CMV: Treatment of persistent or relapsed CMV disease or infection after standard
therapy. For CMV infection, standard therapy is defined as antiviral therapy with
ganciclovir, foscarnet or cidofovir.

- 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 broncheoalveolar lavage fluid in the
presence of new or changing pulmonary infiltrates or changes consistent with
CMV retinitis on ophthalmologic examination.

- CMV infection: defined as the presence of CMV positivity as detected by PCR
or pp65 antigenemia or culture from ONE site such as stool or blood or urine
or nasopharynx.

- Failure of antiviral therapy: 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 pp65 antigenemia after 7 days of antiviral therapy.

2. Adenovirus: Treatment of persistent adenovirus infection or disease despite
standard therapy. Standard therapy is defined as antiviral therapy with cidofovir
or an alternative antiviral agent if patient will not tolerate cidofovir therapy
because of poor renal function.

- Adenovirus infection: defined as the presence of adenoviral positivity as
detected by PCR or culture from ONE site such as stool or blood or urine or
nasopharynx.

- Adenovirus disease: defined as the presence of adenoviral positivity as
detected by PCR, DFA or culture from two or more sites such as stool or
blood or urine or nasopharynx.

- Failure of therapy: 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) after 7 days of antiviral therapy.

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

- EBV infection: defined as Biopsy proven lymphoma with EBV genomes detected
in tumor cells by immunocytochemistry or in situ PCR,Or clinical or imaging
findings consistent with EBV lymphoma and/or elevated EBV viral load in
peripheral blood.

- Failure of therapy is defined as: Increase or less than 50% response at
sites of disease for EBV lymphoma OR, Increase or a fall of less than 50% in
EBV viral load in peripheral blood or any site of disease after 1st dose of
rituximab.

4. BK virus: Treatment of persistent BK virus infection or BK virus disease despite
antiviral treatment with cidofovir or leflunomide. No clear standard treatment is
defined. Cidofovir has been administered in low doses as well as high doses to
HSCT patients with BK infections but no randomized trials are available proving
its clinical efficacy. In small trials leflunomide had activity against BK virus,
therefore we will consider this agent an acceptable alternative to cidofovir,
given the absence of a clear first line option.

- BK virus infection is defined as the presence of BK virus positivity as
detected by PCR or culture in one site such as blood or urine.

- BK virus disease is defined as the presence of BK virus detectable by
culture or PCR in blood or urine or other body fluids and symptoms of
disease including, but not limited to persistent microscopic or macroscopic
hematuria or detectable BK virus in more than one site.

- Failure of therapy 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) or worsening hematuria after 7 days of antiviral
therapy.

5. HHV6: Treatment of persistent HHV6 infection or disease despite antiviral
treatment with ganciclovir, cidofovir and foscarnet. No clear standard treatment
is defined. Ganciclovir, cidofovir and foscarnet all have variable in vitro
activity against HHV-6, and may have a role in treating HHV-6-associated disease
- therefore antiviral treatment with one or more of these agents will we
acceptable initial therapy.

- HHV6 virus infection is defined as the presence of elevated HHV-6 levels as
detected by PCR or positive culture in one site such as CSF or blood.

- HHV6 disease is defined as defined as the presence of HHV6 detectable by
culture or PCR in one or more sites such as blood or CSF and symptoms of
disease including symptoms of HHV6 encephalitis OR detectable HHV6 by PCR or
culture in more than one site.

- Failure of therapy 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) after 7 days of antiviral therapy.

6. JC virus: Treatment of progressive or persistent JC virus infection or disease
without suitable alternative treatment option. Pepmixes specific for antigens on
adenovirus, EBV, CMV, HHV6 and BK virus are used to generate our
multivirus-specific VSTs. No pepmix specific for the rare JC virus is used for
generation of these CTLs, however given the high homology (>90%) between JC and
BK and the fact that BK virus-specific T cells targeting VP1 and Large T (as
targeted in our multivirus VSTs) have been administered to treat JCV-PML,
resulting in viral clearance from the cerebrospinal fluid it is likely that our
VSTs are efficacious against JC virus. Given the current lack of treatment
options for JC virus infection or reactivation after HSCT and the risk of
progression to JML, which is almost uniformly fatal, and the apparent activity of
BK virus-directed T cells against JC virus infected cells, we propose including
patients with progressive or persistent JC virus on this study, unless a suitable
alternative therapy is available.

- JC virus infection is defined as the presence of elevated JC virus levels as
detected by PCR or positive culture in one site such as CSF or blood.

- JC virus disease is defined as defined as the presence of JC virus
detectable by culture or PCR in one or more sites such as blood or CSF and
symptoms of disease including symptoms of PML OR detectable JC virus by PCR
or culture in more than one site.

3. Patients with multiple CMV, EBV, Adenovirus, HHV6 and BK virus infections are eligible
given that each infection is persistent despite standard therapy as defined above.
Patients with multiple infections with one or more reactivation and one or more
controlled infection are eligible to enroll.

4. Clinical status at enrollment to allow tapering of steroids to equal or less than 0.5
mg/kg/day prednisone (or equivalent).

5. HgB>8.0

6. Pulse oximetry of > 90% on room air

7. Available multivirus-specific VSTs

8. Negative pregnancy test in female patients if applicable (childbearing potential who
have received a reduced intensity conditioning regimen).

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

Exclusion Criteria:

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

2. Patients with other 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.

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.

3. Patients who are less than 28 days removed from their allogeneic hematopoieteic stem
cell transplant or who have received donor lymphocyte infusions (DLI) within 28 days.

4. Patients with active acute GVHD grades II-IV.

5. Active and uncontrolled relapse of malignancy