3rd Generation GD-2 Chimeric Antigen Receptor and iCaspase Suicide Safety Switch, Neuroblastoma, GRAIN

We will make iC9-GD2 T cells by infecting normal T cells with a retroviral vector containing the iC9-GD2 gene. After the new gene has been put into the T cells, the cells will be tested to make sure that they kill GD2-positive neuroblastoma cells and then will be either given fresh or frozen until the patient is ready for their infusion.

First, patients will receive cyclophosphamide and fludarabine intravenously (through a needle inserted into a vein or your port-a-cath) for 2 days and then fludarabine alone for one day (Day -4, -3,-2). On the next day (Day -1) patients will receive the drug called pembrolizumab intravenously. Finally on Day 0 patients will be given an infusion of iC9 GD2 T cells into the vein through an IV line at the assigned dose.

The iC9-GD2 T cell infusion will be given by the Center for Cell and Gene Therapy at Texas Children's Hospital or Houston Methodist Hospital. The infusion will take between 5 and 10 minutes. Patients may need to stay in Houston for up to 4 weeks after the infusion so we can monitor them for side effects.

On Day 21 (at the time of the week 3 visit), if the treatment was well tolerated, patients will receive another dose of pembrolizumab intravenously.

There will be follow-up visits every 1-2 weeks during the first 2 months and then they will be spaced out over a total of 15 years. Because the cells are modified with a new gene we must follow patients for at least 15 years to see if there are any long term side effects of gene transfer. During the visits, we will see how the patients are doing and during certain time points we will obtain extra blood samples to learn more about the way the iC9-GD2 T cells are working and how long they last in the body.

After disease re-evaluation, if disease has not gotten worse, or if in the future it seems that patient might benefit and they have not had a severe side effect caused by the infusion of their iC9-GD2 T cells, patients may be eligible to receive up to 2 additional doses of their T cells. Each dose will be at the same dose level as their first infusion and separated by at least 6 weeks such that we can make sure patients have no severe side effects between infusions. If patients receive additional doses of iC9-GD2 T-cells, they may need to stay in Houston for up to 4 weeks after the infusion as well so we can monitor them for side effects. If there were no severe side effects from pembrolizumab, patients will receive pembrolizumab again with the iC9 GD2 T cells on the day before the T cell injection and 21 days after the T cells.

Inclusion criteria

PROCUREMENT

• High risk neuroblastoma with persistent or relapsed disease
• Life expectancy of at least 12 weeks
• Karnofsky/Lansky score of 60% or greater
• Absence of HAMA prior to enrollment (only in patients that have been previously treated with murine antibodies)
• Informed consent and assent (as applicable) obtained from parent/guardian and child

TREATMENT:

• High risk neuroblastoma with persistent or relapsed disease
• Life expectancy of at least 12 weeks
• Karnofsky/Lansky score of 60% or greater
• Patients must have an ANC greater than or equal to 500, platelet count greater than or equal to 20,000
• Pulse Ox greater than or equal to 90% on room air
• AST and ALT less than 5 times the upper limit of normal
• Total bilirubin less than 3 times the upper limit of normal
• 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
• TSH normal for age. Patients using thyroid medication to facilitate a euthyroid state must be on a stable dose for at least 1 month prior to planned infusion
• 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
• 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 activated T-cells with greater than or equal to 20% expression of GD2
• Pembrolizumab available for infusion
• Informed consent and assent (as applicable) obtained from parent/guardian and child

Exclusion criteria

PROCUREMENT:

• Rapidly progressive disease
• History of hypersensitivity to murine protein containing products

TREATMENT:

• 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, tacrolimus or cyclosporine
• Patients previously experienced severe toxicity from cyclophosphamide or fludarabine
• Severe previous toxicity from pembrolizumab or other PD-1 targeted antibody