C7R-GD2.CART Cells for Patients With Relapsed or Refractory Neuroblastoma (GAIL-N)

To prepare the neuroblastoma specific T cells (GD2-C7R T cells), research staff will take
some blood from the patient. We will grow the GD2.C7R T cells by infecting the T cells with a
retroviral vector (a special virus that can carry a new gene into cells) containing one gene
that can recognize and kill neuroblastoma cells (GD2.CAR) and the new gene called C7R that
will help these cells survive longer. After the new genes have been put into the T cells, the
cells will be tested to make sure that they kill GD2-positive neuroblastoma cells.

Because we are growing the cells in the laboratory, we will also need to take blood to test
for infectious viruses such as hepatitis and HIV (the virus that causes AIDS), and we will
also ask patients to complete a questionnaire that is given to blood donors.

The cells generated will be frozen and stored to give back to the patient. Because patients
will have received cells with a new gene in them patients will be followed for a total of 15
years to see if there are any long term side effects of gene transfer.

Patients will be assigned a dose of GD2-C7R T cells. The assigned dose of cells is based on
body weight and height.

In this study, patients will receive the GD2-C7R cells and may also receive cyclophosphamide
and fludarabine. These two drugs are standard chemotherapy medicines and may be given before
the T cells to make space in the blood for the T cells to grow after receiving them.

If the patient receives cyclophosphamide and fludarabine, these drugs will be given
intravenously (through an i.v. needle inserted in a vein or a central line) for 2 days and
then fludarabine alone on the third day.

The patient will be given an injection of GD2-C7R T cells into the vein through an IV line at
the assigned dose. Before receiving the T cell infusion, the patient may be given a dose of
Benadryl (diphenhydramine) and Tylenol (acetaminophen). The infusion will take between 1 and
10 minutes. We will then monitor the patient in the clinic for about 3 hours. The treatment
will be given by the Center for Cell and Gene Therapy at Texas Children's Hospital. The
patient may need to stay in Houston for up to 4 weeks after the infusion so we can monitor
for side effects.

The patient will have follow-up visits after the T cell infusion at weeks 1, 2, 4, 6, and 8,
then at months 3, 6, 9, and 12, and then twice a year for the next 4 years and annually for
the next 10 years for a total of 15 years. The patient will also have scheduled disease
evaluations after the T-cell injection at week 6 and then as clinically needed.

After disease re-evaluation, if the patient's disease has not gotten worse, or if in the
future it seems the patient might benefit AND the patient has not had a severe side effect
caused by the infusion of the GD2-C7R T cells, the patient may be eligible to receive one
additional dose of their T cells. The dose will be at the same dose level as the first
infusion and separated by at least 6 weeks such that we can make sure the patient has no
severe side effects between infusions. If the patient receives an additional dose of GD2-C7R
T-cells, then they will need to stay in Houston for up to 4 weeks after the infusion as well
so we can monitor for side effects.

Medical tests before treatment--

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

- Physical exam

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

- Measurements of the tumor by routine imaging studies and bone marrow evaluation. We will
use the imaging studies that have been used in the past to best assess the tumor
(Computer Tomogram (CT) or Magnetic Resonance Imaging (MRI), and Positron Emission
Tomography (PET/CT), Bone Scan, and/or MIBG scan)

Medical tests during and after treatment--

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

- Physical exams

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

- Measurements of the tumor by routine imaging studies and bone marrow evaluation 6 weeks
after the infusion (if the bone marrow showed tumor before the infusion).

To learn more about the way the GD2-C7R T cells are working and how long they last in the
body, an extra amount of blood will be obtained on the day that chemotherapy starts, the day
of the T-cell infusion(s) and at the end of the T-cell infusion(s), 1, 2, 4, 6 and 8 weeks
after the T-cell infusion(s) and every 3 months for the 1st year, every 6 months for the next
4 years and annually for the next 10 years. The amount of blood taken will be based on 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 one day. This volume is considered safe, but may be decreased
if the patient is anemic (has a low red blood cell count).

During the time points listed above, if the GD2-C7R T cells are found in the patient's blood
at a certain amount, an extra 5 ml (about 1 teaspoon) of blood may need to be collected for
additional testing.

If the patient has a procedure where tumor samples are obtained, like a repeat bone marrow
evaluation or tumor biopsy, we will request a sample to be used for research purposes.

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

Procurement Inclusion Criteria:

1. Evaluable neuroblastoma with persistent or relapsed disease

1. Recurrent disease following completion of aggressive multi-drug frontline
therapy.

2. Progressive disease during aggressive multi-drug frontline therapy.

3. Primary resistant/refractory disease (less than partial response by INRC)
detected at the conclusion of at least 4 cycles of aggressive multi-drug
induction chemotherapy on or according to a standard high-risk treatment protocol

2. Life expectancy of at least 12 weeks

3. Karnofsky/Lansky score of 60% or greater

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

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

6. Greater than 1 and less than 18 years of age

Treatment Inclusion Criteria:

1. Neuroblastoma with persistent or relapsed disease

1. Recurrent disease following completion of aggressive multi-drug frontline
therapy.

2. Progressive disease during aggressive multi-drug frontline therapy.

3. Primary resistant/refractory disease (less than partial response by INRC)
detected at the conclusion of at least 4 cycles of aggressive multi-drug
induction chemotherapy on or according to a standard high-risk treatment protocol

2. Life expectancy of at least 12 weeks

3. Karnofsky/Lansky score of 60% or greater

4. Patients must have an ANC ≥ 500, platelet count ≥ 20,000

5. Pulse Ox ≥ 90% on room air

6. AST and ALT less than 5 times the upper limit of normal

7. Total bilirubin less than 3 times the upper limit of normal

8. Serum creatinine less than 3 times upper limit of normal. Creatinine clearance is
needed for patients with creatinine greater than 1.5 times upper limit of normal.

9. At least 4 weeks from completion and recovered from acute effects of all prior
chemotherapy. If some effects of therapy have become chronic (i.e., treatment
associated thrombocytopenia), the patient must be clinically stable and meet all other
eligibility criteria.

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

11. Patients must have autologous activated T-cells with ≥ 20% expressing GD2.CAR

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

13. Greater than 1 and less than 18 years of age

Procurement Exclusion Criteria:

1. History of hypersensitivity to murine protein containing products

2. History of autoimmune disease (patients with asthma that has not been active for at
least 6 months or patients who only have mild eczema are eligible)

3. Known brain metastases (on evaluation by MIBG and/or PET, CT/MRI/LP not required)

Treatment Exclusion Criteria

1. Currently receiving other investigational drugs.

2. Received any investigational immunotherapies or checkpoint inhibitors within 6 weeks.
Immunotherapies include adoptive cell therapies, gene therapies, and tumor vaccines
for neuroblastoma.

3. History of hypersensitivity to murine protein containing products

4. 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 acceptable limits (LVSF>28% or LVEF>50%).
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. Evidence of tumor potentially causing airway obstruction

6. Patients must not be pregnant, lactating, or unwilling to use birth control

7. Patients must not be currently receiving immunosuppressive drugs such as
corticosteroids (prednisone dose of > 0.25 mg/kg/day or equivalent), tacrolimus or
cyclosporine

8. History of autoimmune disease (patients with asthma that has not been active for at
least 6 months or patients who only have mild eczema are eligible)

9. Known brain metastases (on evaluation by MIBG and/or PET, CT/MRI/LP not required)