NKG2D.Zeta-NK Cell Conditioning With C7R.GD2.CAR-T Cells for Patients With Relapsed or Refractory Osteosarcoma or Neuroblastoma

To make the T cells, the investigators will take patient's blood and stimulate it with growth factors that make T cells grow. Investigators will use a retrovirus to insert the GD2-targeting chimeric antigen receptor (CAR) into the T cells. To make NK cells, investigators will take blood from healthy donors and stimulate them with growth factors that make NK cells grow. Investigators will also use a retrovirus to insert the tumor environment-targeting NK receptor, called NKG2D.zeta, into the NK cells.

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 i15.NKG2D.zeta-NK cells. The assigned dose of cells is based on body weight and height.

In this study, patients will receive the i15.NKG2D.zeta-NK and C7R.GD2.CAR-T cells. On Day -5, the patient will be given an injection of i15.NKG2D.zeta-NK cells into the vein through an IV line at the assigned dose. Before receiving the NK cell infusion, the patient may be given a dose of Benadryl (diphenhydramine) and Tylenol (acetaminophen). The infusion will take between 1 to 10 minutes. Investigators will then monitor the patient in the clinic for about 3 hours. The study was designed to not give doses of lymphodepletion chemotherapy prior to the i15.NKG2D.zeta-NK and C7R.GD2.CAR-T cells. However, some patients may need to receive lymphodepletion chemotherapy prior to the NK cell infusion, based on preliminary study results.

This will be followed by an injection of C7R.GD2.CAR-T cells on Day 0. Before receiving the infusion, the patient may be given doses of Benadryl (diphenhydramine) and Tylenol (acetaminophen). The infusion will take between 1 to 10 minutes. Investigators will 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 day -3, day +3, weeks 1, 2, 3, 4, and 8, then at months 3, 6, 9, an d 12, and then twice a year for the next 4 years and annually for the next 10 years. The patient will also have scheduled disease evaluations after the T cell injection at week 6 and then as clinically needed.

Medical test 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/or bone marrow evaluation. We will use the imaging studies that have been used in the past to best assess the tumor: Computed Tomography (CT) scan, Magnetic Resonance Imaging (MRI), Position Emission Tomography (PET/CT), Bone Scan, and/or MIBG scan.
• Pulmonary Function Tests (PFT) to see how well the patient's lungs are working.

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/or bone marrow evaluation 6 weeks after the infusion (if the bone marrow showed tumor before the infusion).

To learn more about the way the i15.NKG2D.zeta-NK cells and C7R.GD2.CAR-T cells are working and how long they last in the body, an extra amount of blood will be obtained on the day of the NK-cell infusion and the T-cell infusion and at the end of the NK-cell and T-cell infusions, 1, 2, 3, 4, and 8 weeks after the T-cell infusion 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 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 one day. This volume is considered safe, but may be decreased if patient is anemic (has a low red blood cell count).

During the time points listed above, if the i15.NKG2D.zeta-NK cells or C7R.GD2.CAR-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, the investigators 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 medically appropriate.

PROCUREMENT INCLUSION:

• Patients with Neuroblastoma that have persistent disease after standard treatment or have relapsed/refractory disease.

Or

Patients with Osteosarcoma that have persistent disease after standard treatment or have relapsed/refractory disease.

• Karnofsky/Lansky score of 60% or greater.
• Informed consent and assent (as applicable) obtained from parent/guardian and child.
• Greater than 1 year of age.

PROCUREMENT EXCLUSION:

• History of hypersensitivity to murine protein-containing products.
• Known presence of Human Anti-Mouse Antibodies (HAMA).
• Active autoimmune disease (requiring immunosuppressive treatment in the past 6 months).
• Primary brain tumor or known brain metastases (on evaluation by MIBG and/or PET if applicable, CT/MRI/LP not required).

TREATMENT INCLUSION:

• Patients with Neuroblastoma that have persistent disease after standard treatment or have relapsed/refractory disease.

Or

Patients with Osteosarcoma that have persistent disease after standard treatment or have relapsed/refractory disease.

• Karnofsky/Lansky score of 50% or greater
• Pulse Ox greater than or equal to 90% on room air
• AST less than 5 times upper limit of normal (less than 10 times upper normal if known with metastatic liver disease)
• Total bilirubin less than 3 times the upper limit of normal
• Serum creatinine less than 3 times upper limit of normal
• Available autologous T-cells with greater than or equal to 20% expressing GD2.CAR
• Informed consent and assent (as applicable) obtained from parent/guardian and child.
• Greater than 1 year of age.
• Recovered from acute toxic effects of all prior chemotherapy and investigational agents before entering this study.

TREATMENT EXCLUSION:

• History of hypersensitivity to murine protein containing products (patients who have undergone desensitization and successful re-challenge without hypersensitivity reaction are eligible).
• Known presence of Human Anti-Mouse Antibodies (HAMA).
• Tumor potentially causing airway obstruction per investigator discretion.
• Pregnancy or lactation / will not use birth control methods.
• Currently receiving immunosuppressive drugs (patients on low dose corticosteroids are eligible: less than 0.25 mg/kg/day of prednisone/equivalent).
• Primary brain tumor or known brain metastases (on evaluation by MIBG and/or PET if applicable, CT/MRI/LP not required).