CELL INTELLIGENCE · 肿瘤细胞治疗研究

PROCUREMENT INCLUSION:

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

PROCUREMENT EXCLUSION:

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

TREATMENT INCLUSION:

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

TREATMENT EXCLUSION:

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

主要终点：Dose-limiting toxicity (DLT) rate · Proportion of participants with DLTs related to the combination of NK cell and T cell infusions evaluated as per the NCI CTCAE v5.0 criteria · 4 weeks post-CAR-T cell infusion；Maximum tolerated dose (MTD) of i15.NKG2D.zeta-NK cells when given in combination with C7R.GD2.CAR-T cells · The dose level of infused NK cells for which the DLT rate is approximately 0.3 · 4 weeks post CAR-T infusion of the last participant
次要终点：Objective response rate (ORR)；Cytokine release syndrome (CRS) grade

• i15.NKG2D.zeta NK cells and C7R.GD2.CARTs cells · EXPERIMENTAL · Three dose levels will be evaluated. This is a dose escalating trial which will infuse doses of i15.NKG2D.zeta NK cells followed by a fixed dose of C7R.GD2.CAR T cells 5 days later.

The purpose of this study is to find the largest safe dose of i15.NKG2D.zeta-NK cells in combination with C7R.GD2.CAR-T cells, and additionally to evaluate how long they can be detected in patients' blood and what affect they have on patients' cancer. Patients eligible for this study have neuroblastoma or osteosarcoma that expresses a substance on the cancer cells called GD2. This cancer has either come back after treatment or did not respond to the standard or other investigational treatments or therapies used to treat it. There is no standard treatment for these types of advanced cancers at this time. This is a gene transfer research study using special immune cells called NK cells and T cells. NK cells and T cells are types of white blood cell that help the body fight infection. The body has different ways of fighting infection and disease. No single way seems perfect for fighting cancers. This research study combines two different ways of fighting cancer: NK cells and T cells. T cells are special infection-fighting blood cells that can kill cells infected with viruses and tumor cells. NK cells, another kind of infection-fighting cell, can recognize a wide range of cells in distress, including tumor cells and cells that help protect tumor cells in the cancer environment. Both NK cells and T cells have been used individually to treat patients with cancers. They have shown promise, but have not been strong enough individually to cure most patients. Investigators have found from previous research that we can put a new gene into T cells that will make them recognize GD2, a substance found on almost all neuroblastoma and osteosarcoma cells. We can also put a new gene into NK cells that help them fight the tumor environment. Investigators know that T cells and NK cells need substances called cytokines to survive but the cells do not get enough cytokines after infusion into the body; therefore, the investigators have added the genes C7R and IL15 into the T and NK cells, respectively, to give each cell a constant supply of cytokine that helps them to survive longer. The C7R.GD2.CAR-T cells and i15.NKG2D.zeta-NK cells are investigational products not approved by the Food and Drug Administration.