3RD GENERATION GD2 SPECIFIC CHIMERIC ANTIGEN RECEPTOR TRANSDUCED AUTOLOGOUS NATURAL KILLER T-CELLS FOR NEUROBLASTOMA

To prepare the neuroblastoma specific Natural Killer T cells (also called GINAKIT cells),
about 80 mL (up to 6 tablespoons) of blood will be collected from the patient. For children,
the total amount of blood drawn will not be more than 3 ml (less than 1 teaspoon) per 2.2
lbs of body weight.

In case the neuroblastoma specific Natural Killer T cells cannot be expanded from the amount
of blood that can safely be drawn from the patient, the investigators may attempt to collect
white blood cells from the patient by using a special type of blood donation called
leukocyte apheresis. Unlike a regular blood draw or "whole blood" donation in which whole
blood is removed from patient's body, the apheresis process connects the patient to a
machine that removes a particular component of their blood and then returns the rest of the
blood back to them. The white blood cells collected during leukocyte apheresis will be used
to make the GINAKIT cells.

Once collected, the white blood cells will be mixed with a special protein to separate the
Natural Killer T cells from the white blood cells using a special machine called a CliniMACS
Reagent System in the laboratory. This is an investigational device that is not approved by
the FDA. Although this device is not approved for use in this country, it has been in use
for years and is approved in other countries. The investigators will put the new genes into
patient's Natural Killer T cells by mixing them with a retroviral vector (a special virus
that can carry a new gene into cells) containing the new gene called iC9-GD2-CD28-OX40.
After the new gene has been put into the Natural Killer T cells, the cells will be tested to
make sure that they kill GD2-positive neuroblastoma cells and that the cells are killed by
the activation of iC9. The GINAKIT cells may be given back to the patient fresh or frozen.

This is a dose escalation study. This means that at the beginning, patients will be started
on the lowest dose (1 of 4 different levels) of GINAKIT cells. Once that dose schedule
proves safe, the next group of patients will be started at a higher dose. This process will
continue until all 4 dose levels are studied. If the side effects are too severe, the dose
will be lowered or the infusions will be stopped.

Before getting the GINAKIT cells, patients will receive cyclophosphamide and fludarabine
intraveneously for 2 days and then fludarabine alone for one more day. Patients will then
have one day of rest with no chemotherapy before receiving the GINAKIT cells.

The treatment will be given by the Center for Cell and Gene Therapy at Texas Children's
Hospital. Patients will need to stay in Houston for 4 weeks after the infusion so the
investigators can monitor them for side effects. They will have follow-up visits (at weeks
1, 2, 4, 6, and 8; months 3, 6, 9, and 12; twice a year for 4 years and then once a year for
the next 10 years - for a total of 15 years) and scheduled disease evaluations after the
GINAKIT cell infusion (at week 4 and then as clinically needed). Also, to learn more about
the way the GINAKIT cells are working and how long they last in the body, blood will be
obtained before the chemotherapy, on the day of the GINAKIT cell infusion (before and at the
end of the infusion) and at the follow-up visits (time points listed above).

If the patient experiences no significant side effects during or after the first GINAKIT
cell infusion and their cancer remains stable or responds, they may be offered additional
doses of the same cell dose in the future.

Procurement Inclusion Criteria:

- High risk neuroblastoma or persistent or relapsed disease

- Life expectancy of at least 12 weeks

- Age ≥1 and ≤18 years old

- Karnofsky/Lansky score of 60% or greater

- Absence of HAMA prior to enrollment (only in patients that have been previously
treated with murine antibodies)

- Ability to tolerate leukocyte apheresis

- Informed consent for leukocyte apheresis

- Informed consent and assent (as applicable) obtained from parent/guardian and child.

Procurement Exclusion Criteria:

- Rapidly progressive disease

- History of hypersensitivity to murine protein containing products

Treatment Inclusion Criteria:

- High risk neuroblastoma with persistent or relapsed disease

- Life expectancy of at least 12 weeks

- Age ≥1 and ≤18 years old

- Karnofsky/Lansky score of 60% or greater

- Patients must have an ANC ≥ 500 without the use G-CSF or GM-CSF for at least 48hrs,
platelet count ≥ 20,000

- Pulse Ox ≥ 90% on room air

- AST less than 5 times the upper limit of normal

- Bilirubin less than 3 times the upper limit of normal

- Serum creatinine less than 3 times upper limit of normal

- Recovered from the acute toxic effects of all prior chemotherapy (if some effects of
chemotherapy are expected to last long term, patient is eligible if meeting other
eligibility criteria).

- Absence of human anti-mouse antibodies (HAMA) prior to enrollment for patients who
have received prior therapy with murine antibodies

- Patients must have autologous transduced NKTs with greater than or equal to 20%
expression of GD2-specific CAR.

- Informed consent and assent (as applicable) obtained from parent/guardian and child.

Treatment Exclusion Criteria:

- Rapidly progressive disease

- Currently receiving other investigational drugs

- History of hypersensitivity to murine protein containing products

- History of cardiomegaly or bilateral pulmonary infiltrates on chest radiograph or CT.
However, patients with cardiomegaly on imaging may be enrolled if they have an
assessment of cardiac function (i.e., ECHO or MUGA) within 3 weeks of starting
protocol therapy that is within normal limits. Additionally, patients with bilateral
pulmonary infiltrates on imaging may be enrolled if the lesions are not consistent
with active neuroblastoma (i.e., negative on functional imaging with PET or MIBG, or
by pathologic assessment).

- Evidence of tumor potentially causing airway obstruction

- Patients who are pregnant, lactating, or unwilling to use birth control

- Patients currently receiving immunosuppressive drugs such as corticosteroids(Patients
may receive treatment if treated with corticosteroids with dose of less than
0.5mg/kg/day of prednisone equivalent), tacrolimus or cyclosporine.

- Patients who have previously experienced severe toxicity from cyclophosphamide and
fludarabine.

- All labs must be collected within 10 days prior to initiation of study related
treatment (except for verification of GD2 transduction)