Neoplasms

All Conditions

Rare Diseases

Neuroblastoma

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Neuroepithelial

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Gaucher Disease Type 2

Neuroepithelioma

GINAKIT cells will be administer to patients with Neuroblastomas on Day 0.

Six dose levels of GINAKIT cells will be studied. Dosing will be based on the actual number of transduced cells. All doses are per m2.

* Dose Level 1 = 3 x 10\^6
* Dose Level 2 = 1 x 10\^7
* Dose Level 3 = 3 x 10\^7
* Dose Level 4 = 1 x 10\^8
* Dose Level 5 = 3 x 10\^8
* Dose Level 6 = 1 x 10\^9

GINAKIT Cells

Andras Heczey, MD

Ramy Sweidan

This research study combines two different ways of fighting cancer: antibodies and Natural Killer T cells (NKT). Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special white blood cells that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. Investigators have found from previous research that they can put a new gene into T cells that will make them recognize cancer cells and kill them. In a previous clinical trial, investigators made artificial genes called a chimeric antigen receptors (CAR), from an antibody called 14g2a that recognizes GD2, a molecule found on almost all neuroblastoma cells (GD2-CAR). Investigators put these genes into the patients' own T cells and gave them back to patients that had neuroblastoma.

NKT cells are another special subgroup of white blood cells that can specifically go into tumor tissue of neuroblastoma. Inside the tumor, there are other white blood cells called macrophages which help the cancer cells to grow and recover from injury. NKT cells can specifically kill these macrophages and slow the tumor growth.

We will expand NKT cells and add GD2-specific chimeric antigen receptors to the cells. We think these cells might be better able to attack NB since they also work by destroying the macrophages that allows the tumor to grow. The chimeric antigen receptor will also contain a gene segment to make the NKT cells last longer. This gene segment is called CD28. In addition, to further improve the antitumor activity of the GINAKIT cells we added another gene expressing a molecule called Interleukin -15 (IL-15). The combination of these 3 components showed the most antitumor activity by CAR expressing NKT cells and improved these cells' survival in animal models.

GD2-CAR expressing NKTs have not been tested in patients so far. The purpose of this study is to find the largest effective and safe dose of GD2-CAR NKT cells (GINAKIT cells), to evaluate their effect on the tumor and how long they can be detected in the patient's blood and what affect they have on the patient's neuroblastoma.

In this study the first step is to collect blood from the patient to make the GINAKIT cells. Once the GINAKIT cells are made they will be administered to the patient.

This is a dose escalation study. This means that at the beginning, patients will be started on the lowest dose (1 of 6 different levels) of GINAKIT cells. Once that dose schedule proves safe, the next group of patients will be started at a higher dose. This process will continue until all 6 dose levels are studied. If the side effects are too severe, the dose will be lowered or the infusions will be stopped.

Before getting the GINAKIT cells, the patient will receive cyclophosphamide and fludarabine intravenously (through a needle inserted into a vein or the patient's port-a-cath) for 2 days and then fludarabine alone for one more day. The patient will then have one day of rest with no chemotherapy before receiving the GINAKIT cells.

The patient will be given an injection of GINAKIT cells into the vein through an IV line at the assigned dose. Before the patient receives the injection, they may be given a dose of Benadryl (diphenhydramine) and Tylenol (acetaminophen). The injection will take up to 10 minutes. The patient will be monitored in the clinic after the injection for about 4 hours. The treatment will be given by the Center for Cell and Gene Therapy at Texas Children's Hospital.

The patient will need to stay in Houston for 4 weeks after the infusion so investigators can monitor the patient for side effects. The patient will have follow-up visits (at weeks 1, 2, 3, 4 and 8; months 3, 6, 9, and 12; twice a year for 4 years and then once a year for the next 10 years - for a total of 15 years) and scheduled disease evaluations after the GINAKIT cell infusion (at week 6 and then as clinically needed).

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

* Physical exam
* Blood tests to measure blood cells, kidney and liver function
* Buccal swabs (cheek scraping)
* Measurements of your tumor by routine imaging studies and bone marrow evaluation within 4 weeks (preferably 2 weeks) before start of lymphodepletion (no other cancer treatment should be given after these studies and the GINAKIT cell infusion). Imaging studies that have been used in the past to best assess your tumor will be used (Computer Tomogram (CT) or Magnetic Resonance Imaging (MRI), and Positron Emission Tomography (PET/CT), and/or MIBG scan). A PET scan is an imaging test that uses radioactive material to look for disease in the body. A MIBG scan is an imaging test that uses radioactive material and a special scanner to find or confirm the presence of neuroblastoma.

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

* Physical exams
* Blood tests to measure blood cells counts, kidney and liver function.
* Measurements of the patient's tumor by routine imaging studies 4-6 weeks after the infusion.
* Tumor biopsy at 2 weeks and between 4-6 weeks after the infusion and as clinically indicated thereafter. The evaluation at week 2 after the infusion is for research only and is done to see whether or not there are GINAKIT cells in the tumor. For all clinically indicated tumor biopsies a portion of the sample for research will be requested.
* If a tumor was in the bone marrow at the time of treatment, the procedure will be repeated at 2 weeks and between 4-6 weeks after the infusion and as clinically indicated thereafter. The evaluation at week 2 after the infusion is for research only and is done to see whether or not there are GINAKIT cells in the bone marrow. For all clinically indicated bone marrow collections a portion of the sample for research will be requested.

To learn more about the way the GINAKIT cells are working and how long they last in the body, an extra amount of blood will be obtained before the chemotherapy, on the day of the GINAKIT cell infusion (before and at the end of the infusion), 1, 2, 3, 4 and 8 weeks after the GINAKIT cell infusion, every 3 months for the 1st year, every 6 months for the next 4 years and then once a year for the next 10 years (for a total of 15 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 given day. This volume is considered safe, but may be decreased if the patient is anemic (have a low red blood cell count). This blood will also be used to monitor your white blood cell levels. In the event your white blood cell counts are high, you will be admitted to the hospital where you will be treated with hydration, steroids or chemotherapy. The study doctor will discuss with you the best treatment options.

During the time points listed above, if the GINAKIT cells are found in the patient's blood at a certain amount, an extra 5ml of blood may need to be collected for additional testing.

If the patient has a procedure where tumor samples are obtained, investigators will request a sample to be used for research purposes.

If the patient develops a second abnormal growth, significant blood or nervous system disorder during the trial, a biopsy sample of the tissue will be tested (if a sample can be obtained).

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

Because the patient will receive cells with a new gene in them they will be followed for a total of 15 years to see if there are any long term side effects of gene transfer.

GD2 Specific CAR and Interleukin-15 Expressing Autologous NKT Cells to Treat Children With Neuroblastoma

GD2 Specific Chimeric Antigen Receptor (CAR) and Interleukin-15 Expressing Autologous Natural Killer T-cells to Treat Children With Neuroblastoma

Summarize at pre- and post-infusion time points using descriptive statistics to evaluate their expansion and persistence. Changes in each of these NKTs from pre-infusion to each time point of post-infusion will be assessed and compared.

Defined as the highest dose level that will have at most a 33% chance of inducing the following NKT-cell-related dose limiting toxicities (DLTs) within 28 days after infusion of NKTs.

Summarize tumor response by calculating overall response rates and report the Kaplan-Meier curves for the relapse-free survival.

Center for Cell and Gene Therapy, Baylor College of Medicine

Baylor College of Medicine

Assistant Professor

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Patients receive chemotherapy with Fludarabine and Cyclophosphamide and then an infusion of the GINAKIT cells (iC9-GD2.CD28.OX40.zeta Natural Killer T cells)

500 mg/m2/day x 2 days; for patients \<12 kg the dose is 16.7 mg/kg/day x 2 days; Cyclophospamide will be given daily starting Day -4 prior to administration of GINAKIT cells.

cyclophosphamide

30 mg/m2/day x 3 days; for patients \<12 kg the dose is 1 mg/kg/day x 3 days; Fludarabine will be given daily starting Day -4 prior to administration of GINAKIT cells

* Dose Level 1 = 3 x 10\^6
* Dose Level 2 = 1 x 10\^7
* Dose Level 3 = 3 x 10\^7
* Dose Level 4 = 1 x 10\^8

After the end of the 4 week evaluation period, if subjects have not had a severe side effects and if disease has not gotten worse, the subjects may be offered additional doses of the same cell dose in the future.

Andras A Heczey, MD

This research study is for patients that have a cancer called Neuroblastoma that has either come back after treatment or did not respond to the standard medicines used to treat it. This study combines two different ways of fighting cancer: antibodies and Natural Killer T cells. Antibodies are types of proteins that protect the body from infectious diseases and possibly cancer. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including cells infected with viruses and tumor cells. Both antibodies and T cells have been used to treat patients with cancers. The investigators have found from previous research that they can put a new gene into T cells that will make them recognize cancer cells and kill them. In a previous clinical trial, the investigators made a gene called a chimeric antigen receptor (CAR), from an antibody called 14g2a that recognizes GD2, a molecule found on almost all neuroblastoma cells (GD2-CAR). They put this gene into the patients' own T cells and gave them back to patients that had neuroblastoma. Nineteen patients were treated on that study and there were no long term side-effects seen after the GD2 T cell infusion. As the investigators have followed the patients over time, they noticed that for those patients with disease at the time of their infusion, the time to progression (the amount of time it takes before their neuroblastoma got worse) was longer in those whom they could find GD2 T cells in the blood for more than 6 weeks after the last T cell infusion. Because of this, the investigators think that if effector cells are able to last longer, they may have a better chance of killing neuroblastoma tumor cells.

Natural Killer T cells are a special subset of innate lymphocytes that can effectively go into tumor tissues of neuroblastoma. Inside the tumor, there are certain white blood cells which help the cancer cells to grow and recover from injury. Natural Killer T-cells can specifically kill these cells. In this study, Natural Killer T cells will be genetically engineered to express GD2-CAR to attack neuroblastoma cells and the white blood cells inside the tumor tissue.

To prepare the neuroblastoma specific Natural Killer T cells (also called GINAKIT cells), about 80 mL (up to 6 tablespoons) of blood will be collected from the patient. For children, the total amount of blood drawn will not be more than 3 ml (less than 1 teaspoon) per 2.2 lbs of body weight.

In case the neuroblastoma specific Natural Killer T cells cannot be expanded from the amount of blood that can safely be drawn from the patient, the investigators may attempt to collect white blood cells from the patient by using a special type of blood donation called leukocyte apheresis. Unlike a regular blood draw or "whole blood" donation in which whole blood is removed from patient's body, the apheresis process connects the patient to a machine that removes a particular component of their blood and then returns the rest of the blood back to them. The white blood cells collected during leukocyte apheresis will be used to make the GINAKIT cells.

Once collected, the white blood cells will be mixed with a special protein to separate the Natural Killer T cells from the white blood cells using a special machine called a CliniMACS Reagent System in the laboratory. This is an investigational device that is not approved by the FDA. Although this device is not approved for use in this country, it has been in use for years and is approved in other countries. The investigators will put the new genes into patient's Natural Killer T cells by mixing them with a retroviral vector (a special virus that can carry a new gene into cells) containing the new gene called iC9-GD2-CD28-OX40. After the new gene has been put into the Natural Killer T cells, the cells will be tested to make sure that they kill GD2-positive neuroblastoma cells and that the cells are killed by the activation of iC9. The GINAKIT cells may be given back to the patient fresh or frozen.

This is a dose escalation study. This means that at the beginning, patients will be started on the lowest dose (1 of 4 different levels) of GINAKIT cells. Once that dose schedule proves safe, the next group of patients will be started at a higher dose. This process will continue until all 4 dose levels are studied. If the side effects are too severe, the dose will be lowered or the infusions will be stopped.

Before getting the GINAKIT cells, patients will receive cyclophosphamide and fludarabine intraveneously for 2 days and then fludarabine alone for one more day. Patients will then have one day of rest with no chemotherapy before receiving the GINAKIT cells.

The treatment will be given by the Center for Cell and Gene Therapy at Texas Children's Hospital. Patients will need to stay in Houston for 4 weeks after the infusion so the investigators can monitor them for side effects. They will have follow-up visits (at weeks 1, 2, 4, 6, and 8; months 3, 6, 9, and 12; twice a year for 4 years and then once a year for the next 10 years - for a total of 15 years) and scheduled disease evaluations after the GINAKIT cell infusion (at week 4 and then as clinically needed). Also, to learn more about the way the GINAKIT cells are working and how long they last in the body, blood will be obtained before the chemotherapy, on the day of the GINAKIT cell infusion (before and at the end of the infusion) and at the follow-up visits (time points listed above).

If the patient experiences no significant side effects during or after the first GINAKIT cell infusion and their cancer remains stable or responds, they may be offered additional doses of the same cell dose in the future.

3RD GENERATION GD2 SPECIFIC CHIMERIC ANTIGEN RECEPTOR TRANSDUCED AUTOLOGOUS NATURAL KILLER T-CELLS FOR NEUROBLASTOMA

3RD GENERATION GD2 SPECIFIC CHIMERIC ANTIGEN RECEPTOR AND INDUCIBLE CASPASE 9 SAFETY SWITCH TRANSDUCED AUTOLOGOUS NATURAL KILLER T-CELLS TO TREAT CHILDREN WITH NEUROBLASTOMA (GINAKIT)

We will assess the MTD and the toxicity of GINAKIT cells adoptively transferred to patients with relapsed/refractory neuroblastoma

We will:

* evaluate residual disease sites for change of dimensions of tumor mass by 3 dimensional imaging (MRI or CT) after the administration of GINAKIT cells;
* Determine the number of detectable MIBG avid disease or bone scan positive sites in response to the administration of GINAKIT cells;
* Assess bone marrow clearance among children with bone marrow involvement at the time of enrollment after the administration of GINAKIT cells

We will assess:

* The expansion and functional persistence of GINAKIT cells in the peripheral blood of patients using transgene detection by quantitative real-time PCR, flow cytometry and response of transgenic cells to tumor antigen;
* The frequency of NKT target cells: CD1d+CD33+CD14+CD16+/- myelomonocytic cells in blood and CD1d+CD33+CD14+CD163+ (M2-polarized) TAMs in tumor biopsies and BM aspirates (when available)
* The frequency and activation status (CD69) of NK cells (CD3-CD56+)
* The sequential changes in patients' serum cytokine and chemokine levels after infusion of GINAKIT cells

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
GD2 Specific CAR and Interleukin-15 Expressing Autologous NKT Cells to Treat Children With Neuroblastoma	NCT03294954	Neuroblastoma	GINAKIT Cells	1 Year - 21 Years	Baylor College of Medicine
3RD GENERATION GD2 SPECIFIC CHIMERIC ANTIGEN RECEPTOR TRANSDUCED AUTOLOGOUS NATURAL KILLER T-CELLS FOR NEUROBLASTOMA	NCT02439788	Neuroblastoma	cyclophosphamid... Fludarabine GINAKIT Cells	1 Year - 18 Years	Baylor College of Medicine

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