Treatment of Relapsed or Refractory Neuroblastoma With Expanded Haploidentical NK Cells and Hu14.18-IL2

Natural Killer cells, a type of white blood cell, circulate around the body and kill abnormal
cells (cells that are malignant, damaged or infected with virus). Sometimes cancer cells
adapt to the body's own NK cells and are able to avoid being killed by them. This clinical
trial uses two strategies to overcome the cancer cells' ability to avoid NK cell-mediated
death.

The first strategy involves giving NK cells from another individual to the patient (in other
words, donor- or haploidentical-NK cells). This is done because NK cells from an individual
who is haploidentical (half-matched genetic make-up) are still able to effectively kill the
cancer cells. Unfortunately, only a limited number of NK cells can be obtained from a donor.
So, to increase the number of cancer-killing NK cells that will be given to the patient, the
donor NK cells will first be grown in a sterile laboratory environment and allowed to
multiply many-fold before they are infused into the patient. This growing process also
activates the donor NK cells, which increases their ability to kill cancer cells.

The second strategy to overcome the cancer cells' ability to avoid NK cell-mediated death is
to administer the immunocytokine, hu14.18-IL2, every day for seven days after infusion of the
donor NK cells. The antibody portion (hu14.18) of the immunocytokine molecule "flags" the
neuroblastoma cells for destruction by NK cells and the cytokine portion (IL2) further
activates the NK cells (as well as other anti-tumor immune effector cells).

Since the donor NK cells are from a haploidentical individual, they are different enough to
be recognized as foreign cells and will be killed immediately ("rejected") by the patients
own immune system unless the immune system is restrained. So, to allow the donor NK cells
time to kill neuroblastoma cells before they are "rejected", a chemotherapy regimen is first
given to the patient to temporarily restrain the patient's own immune system. This also
allows "room" for the donor NK cells to live, multiply and function.

Four courses of treatment are planned for each subject. Each course of treatment will be
approximately one month long and involves a week of chemotherapy followed by infusion of
donor NK cells. Beginning the day after the donor NK cell infusion, hu14.18-IL2 is infused
over four hours for seven consecutive days.

Inclusion Criteria:

- Relapsed or refractory neuroblastoma

- Karnofsky/Lansky performance score > 50

- Life expectancy ≥ 4 months

- Creatinine clearance or radioisotope GFR ≥ 60 ml/min/1.73m2 OR serum creatinine within
normal limits based on age and gender

- ANC ≥ 750/µL

- Platelet count ≥ 50,000/µL

- Hemoglobin ≥ 8 g/dL

- Total bilirubin ≤ 1.5 x upper limit of normal for age

- ALT (SCPT) ≤ 5 x upper limit of normal for age

- Shortening fraction of ≥ 27% by echocardiogram OR Ejection fraction of ≥55% by MUGA

- No evidence of dyspnea at rest

- Pulse oximetry > 94% on room air

- CNS toxicity ≤ Grade 2

- Patients with seizure disorders may be enrolled if seizures are well controlled on
anticonvulsant therapy

- >100 days after autologous stem cell infusion following myeloablative therapy

- > 2 weeks since chemotherapy

- ≥ 6 months if prior craniospinal axis XRT (> 50%)

- ≥ 6 months if > 50% radiation of pelvis

- ≥ 6 weeks after therapeutic 131-I-MIBG

- Informed consent obtained (patient or legal representative)

- Women of reproductive potential must have negative pregnancy test and be willing to
use effective birth control method

- Suitable haploidentical donor must be available

- No evidence of CNS (central nervous system) disease in patients with a history of CNS
disease

- > 1 week since growth factor(s)

Exclusion Criteria:

- Prior history of ventilator support related to lung injury

- Symptomatic pleural effusions or ascites

- < 2 weeks after major surgery

- History of anaphylaxis while receiving prior anti-GD2 therapy

- Pregnant

- HIV infection

- Heart failure or uncontrolled cardiac rhythm disturbance

- Active infection

- Prior organ allograft

- Prior allogeneic bone marrow or peripheral blood stem cell transplant

- Significant serious intercurrent illnesses expected to interfere with the anti-tumor
effect of treatment or to significantly increase the severity of toxicities
experienced for treatment

- Any mental or physical condition, in the opinion of the PI (or PI designee), which
could interfere with the ability of the subject (or the only parent or legal guardian
available to care for the subject) to understand or adhere to the requirements of the
study.

- Enrollment in any other clinical study from screening up to Day 28 after the last
treatment on this study (unless PI judges such enrollment would not interfere with
endpoints of this study)