CD19.CAR-multiVSTs for Patients With CD19+ B-ALL or NHL Undergoing Related Allogeneic HSCT (CARMA)

First, a donor gave us blood to make CD19 chimeric receptor multivirus specific T cells in
the laboratory. These cells are grown and frozen for the patient. To make these special T
cells, they are first stimulated with proteins specific for the target 5 viruses, then grow
them with stimulator cells. These stimulator cells are irradiated (exposed to X ray waves in
the laboratory) so that they can no longer grow. The proteins help the T cells learn to see
and attack cells infected with CMV, EBV, Adv, BKV and HHV-6 (the target 5 viruses).

To get the CD19 antibody to attach to the surface of the T cell, the antibody gene is
inserted into the T cell. This is done with a virus called a retrovirus that has been made
for this study and will carry the antibody gene into the T cell. This virus also helps us
find the T cells in the blood after injection. Once a sufficient number of T cells are made,
they are frozen and tested to make sure they kill CD19+ tumor cells and cells infected with
CMV, EBV, Adv, BKV and HHV-6 in the laboratory. The investigators will also test the cells to
make sure they don't kill other normal cells in the body. Once testing is completed the cells
will be ready to give to the patient.

Because the patient will have received cells with a new gene in them, the patient will be
followed for a total of 15 years to see if there are any long term side effects of gene
transfer. Because this is what is called a dose-escalation study, the investigators will be
testing 3 different doses of T cells to find out which dose is safe, and possibly beneficial.
When patients enroll on this study, they will be assigned a dose of CD19 chimeric receptor
multivirus specific T cells. The dose received depends on the number of patients who have
been treated before the patient, and how well they tolerated the T cells.

Patients will be given an injection of cells into the vein through an IV line at the assigned
dose. Before they receive the injection, they may be given a dose of diphenhydramine
(Benadryl) and acetaminophen (Tylenol). The injection will take about 10 minutes. The
investigators will follow the patient in the clinic after the injection for up to 4 hours.
Alternatively, if the patient has a high level of leukemia or lymphoma in the body, the
investigators may decide to monitor the patient in the hospital after the injection. Patients
will be required to remain local for at least 3 weeks after the T cell injection. This will
be discussed before the treatment. The treatment will be given by the Center for Cell and
Gene Therapy at Texas Children's Hospital or Houston Methodist Hospital.

Medical tests before treatment— Patients will receive a series of standard medical tests
including physical exam and blood tests to measure blood cells, kidney and liver function.

Medical tests during and after treatment— Patients will receive standard medical tests when
they are getting the infusions and after including physical exams and blood tests to measure
blood cells, kidney and liver function.

To learn more about the way the CD19 chimeric receptor multivirus specific T cells are
working and how long they last in the body, extra blood will be drawn. This blood may be
drawn from a central line (existing long-term IV) if the patient has one. On the day patients
receive the cells, blood will be taken before the cells are given and 3 hours afterwards.
Other blood will be drawn one week, 2 weeks, 4 weeks, 6 weeks and 8 weeks after the infusion,
then at Months 3, 6, 9 and 12. Because patients have had a bone marrow transplant, the
majority of these time points would require a blood draw to check the standard medical tests
anyway. However, some of these time points may involve an extra trip to clinic and blood
draw. Then blood will be drawn every 6 months for 4 years, then yearly for a total of 15
years (up to 30 blood collections). If patients receive the cells at a time when sensitive
tests indicate relapse or a high risk of relapse, patients will have additional reviews and
blood tests to monitor these tests and look for relapse.

Patients will receive supportive care for acute (short) or chronic (long-term) toxicity,
including blood components or antibiotics, and other intervention as appropriate.

Inclusion Criteria:

1. Diagnosis of CD19+ B-ALL or NHL undergoing related allogeneic HSCT, with no evidence
of disease post-HSCT (Group A) OR minimal residual disease (MRD) at time of HSCT OR
relapse post-HSCT (Group B).

Morphologic relapse (for Group B) will be defined by accepted definitions in Section
5.6 of the full protocol, and measured by PCR positivity, specific cytogenetic
abnormalities, an abnormal population on flow cytometry or increased blasts on bone
marrow biopsy or in the peripheral blood.

MRD will be defined as detection in blood or marrow of any of the following (at time
of transplant or on post-transplant evaluation): a) Any leukemia specific marker (such
as t(9:22) or t(4:11)) documented in the patient's leukemia cells pre-transplant on a
post-transplant evaluation b) An immune globulin rearrangement known to be a disease
marker for this patient c) A leukemia specific phenotype at a level of > 0.01%95, 96
d) Mixed donor chimerism.

2. Age ≤ 75 years old

3. Patients with life expectancy ≥ 12 weeks

4. Patients with a Karnofsky/Lansky score ≥ 60

5. Related Donor approved for stem cell transplant

6. Patient or parent/guardian capable of providing informed consent

7. Patients with bilirubin less than or equal to 2x upper limit of normal

8. AST less than or equal to 3x upper limit of normal

9. Creatinine ≤2x upper limit of normal for age

10. Hemoglobin >7.0 (can be a transfused value)

11. Pulse oximetry of >90% on room air

12. Sexually active patients must be willing to utilize one of the more effective birth
control methods for 6 months after the CTL infusion. The male partner should use a
condom.

13. Available stem cell donor-derived CD19-CAR transduced multi-virus-specific cytotoxic T
lymphocytes with 15% expression of CD19-CAR determined by flow-cytometry and <10%
cytotoxicity against patient or donor-derived (or other family member-derived) PHA
blasts.

Exclusion Criteria:

1. Severe intercurrent infection: Patients with a concurrent bacterial infection 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 antifungal 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.

2. Evidence of graft versus host disease >grade II

3. Pregnant or lactating

4. History of hypersensitivity reactions to murine protein-containing products.

5. Currently taking corticosteroids for therapy of GVHD at a dose of >0.5mg/kg prednisone
equivalent.

6. CNS abnormalities: Presence of CNS-3 disease defined as detectable cerebrospinal blast
cells in a sample of CSF with ≥ 5 WBCs per mm3; History or presence of any CNS
disorder such as a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia,
cerebellar disease, or any autoimmune disease with CNS involvement.

7. Patients who have received donor lymphocyte infusion (DLI) within 28 days.