GD2 Specific CAR and Interleukin-15 Expressing Autologous NKT Cells to Treat Children With Neuroblastoma

In this study the first step is to collect blood from the patient to make the GINAKIT cells.
Once the GINAKIT cells are made they will be administered to the patient.

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, the patient will receive cyclophosphamide and fludarabine
intravenously (through a needle inserted into a vein or the patient's port-a-cath) for 2 days
and then fludarabine alone for one more day. The patient will then have one day of rest with
no chemotherapy before receiving the GINAKIT cells.

The patient will be given an injection of GINAKIT cells into the vein through an IV line at
the assigned dose. Before the patient receives the injection, they may be given a dose of
Benadryl (diphenhydramine) and Tylenol (acetaminophen). The injection will take up to 10
minutes. The patient will be monitored in the clinic after the injection for about 4 hours.
The treatment will be given by the Center for Cell and Gene Therapy at Texas Children's
Hospital.

The patient will need to stay in Houston for 4 weeks after the infusion so investigators can
monitor the patient for side effects. The patient will have follow-up visits (at weeks 1, 2,
3, 4 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 6 and then as clinically needed).

Before being treated, the patient will receive a series of standard medical tests as follows:

- Physical exam

- Blood tests to measure blood cells, kidney and liver function

- Measurements of your tumor by routine imaging studies and bone marrow evaluation within
4 weeks (preferably 2 weeks) before treatment study entry (no other cancer treatment
should be given after these studies and the GINAKIT cell infusion). Imaging studies that
have been used in the past to best assess your tumor will be used (Computer Tomogram
(CT) or Magnetic Resonance Imaging (MRI), and Positron Emission Tomography (PET/CT),
and/or MIBG scan). A PET scan is an imaging test that uses radioactive material to look
for disease in the body. A MIBG scan is an imaging test that uses radioactive material
and a special scanner to find or confirm the presence of neuroblastoma.

The patient will receive standard medical tests when they are getting the infusions and
afterwards as follows:

- Physical exams

- Blood tests to measure blood cells counts, kidney and liver function.

- Measurements of the patient's tumor by routine imaging studies 4-6 weeks after the
infusion.

- Tumor biopsy at 2 weeks and between 4-6 weeks after the infusion and as clinically
indicated thereafter. The evaluation at week 2 after the infusion is for research only
and is done to see whether or not there are GINAKIT cells in the tumor. For all
clinically indicated tumor biopsies a portion of the sample for research will be
requested.

- If a tumor was in the bone marrow at the time of treatment, the procedure will be
repeated at 2 weeks and between 4-6 weeks after the infusion and as clinically indicated
thereafter. The evaluation at week 2 after the infusion is for research only and is done
to see whether or not there are GINAKIT cells in the bone marrow. For all clinically
indicated bone marrow collections a portion of the sample for research will be
requested.

To learn more about the way the GINAKIT cells are working and how long they last in the body,
an extra amount of blood will be obtained before the chemotherapy, on the day of the GINAKIT
cell infusion (before and at the end of the infusion), 1, 2, 3, 4 and 8 weeks after the
GINAKIT cell infusion, every 3 months for the 1st year, every 6 months for the next 4 years
and then once a year for the next 10 years (for a total of 15 years). The amount of blood
taken will be based on the patient's weight with up to a maximum of 60 ml (12 teaspoons) of
blood to be obtained at any one time. For children, the total amount of blood drawn will not
be more than 3 ml (less than 1 teaspoon) per 1 kg of body weight on any given day. This
volume is considered safe, but may be decreased if the patient is anemic (have a low red
blood cell count).

During the time points listed above, if the GINAKIT cells are found in the patient's blood at
a certain amount, an extra 5ml of blood may need to be collected for additional testing.

If the patient has a procedure where tumor samples are obtained, investigators will request a
sample to be used for research purposes.

If the patient develops a second abnormal growth, significant blood or nervous system
disorder during the trial, a biopsy sample of the tissue will be tested (if a sample can be
obtained).

The patient will receive supportive care for any acute or chronic toxicities, including blood
components or antibiotics, and other intervention as appropriate.

Because the patient will receive cells with a new gene in them they will be followed for a
total of 15 years to see if there are any long term side effects of gene transfer.

Procurement Inclusion Criteria:

1. Relapsed or refractory high risk neuroblastoma

2. Life expectancy of at least 12 weeks

3. Age greater than 1 year and less than 21 years old

4. Karnofsky/Lansky score of 60% or greater

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

6. Ability to tolerate leukocyte apheresis

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

8. Patients must have an ANC greater than or equal to 500/µl #, platelet count greater
than or equal to 20,000/µl. Patients may be transfused to obtain a platelet count
greater than or equal to 20,000/µl.

9. Pulse Ox greater than or equal to 90% on room air

10. Serum AST less than 3 times the upper limit of normal

11. Total Bilirubin less than 1.5 times the upper limit of normal

12. Serum creatinine normal for age

13. Recovered from the acute toxic effects of all prior chemotherapy based on the
enrolling physician's assessment (if some effects of chemotherapy are expected to last
long term, patient is eligible if meeting other eligibility criteria).

14. Weight greater than 12kg

Procurement Exclusion Criteria:

1. Rapidly progressive disease

2. History or hypersensitivity to murine protein-containing products

3. Tumor causing airway obstruction

4. Currently receiving immunosuppressive drugs such as corticosteroids$, tacrolimus or
cyclosporine

5. Severe previous toxicity from cyclophosphamide or fludarabine based on the enrolling
physician's assessment

6. HIV infection

- ANC ≥ 500 without the use G-CSF or GM-CSF for at least 48hrs. $: Patients may
receive treatment if treated with corticosteroids with dose of less than
0.5mg/kg/day of prednisone equivalent.

Treatment Inclusion Criteria:

1. Relapsed or refractory high risk neuroblastoma

2. Life expectancy of at least 12 weeks

3. Age greater than 1 year and less than 21 years old

4. Karnofsky/Lansky score of 60% or greater

5. Patients must have an ANC greater than or equal to 500/µl #, platelet count greater
than or equal to 20,000/µl. Patients may be transfused to obtain a platelet count
greater than or equal to 20,000/µl.

6. Pulse Ox greater than or equal to 90% on room air

7. Serum AST less than 3 times the upper limit of normal

8. Pulse Bilirubin less than 1.5 times the upper limit of normal

9. Serum creatinine normal for age

10. Recovered from the acute toxic effects of all prior chemotherapy based on the
enrolling physician's assessment (if some effects of chemotherapy are expected to last
long term, patient is eligible if meeting other eligibility criteria and expected to
tolerate lymphodepletion).

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

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

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

14. Weight greater than 12kg

Treatment Exclusion Criteria:

1. Rapidly progressive disease

2. Currently receiving any investigational drugs

3. History or hypersensitivity to murine protein-containing products

4. 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).

5. Tumor potentially causing airway obstruction

6. Pregnancy or lactation or not willing to use birth control

7. Currently receiving immunosuppressive drugs such as corticosteroids$, tacrolimus or
cyclosporine

8. Severe previous toxicity form cyclophosphamide or fludarabine based on the enrolling
physician's assessment

9. HIV infection

- All labs must be collected within 10 days prior to initiation of study related
treatment (except for verification of GD2 transduction) #: ANC ≥ 500/µl without
the use G-CSF or GM-CSF for at least 48hrs. $: Patients may receive treatment if
treated with corticosteroids with dose of less than 0.5mg/kg/day of prednisone
equivalent.