GD2 Specific Chimeric Antigen Receptor (CAR) and Interleukin-15 Expressing Autologous Natural Killer T-cells to Treat Children With Neuroblastoma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 70
- 试验地点
- 1
- 主要终点
- Maximum tolerated dose of autologous NKTs expressing a 2nd generation GD2-specific chimeric antigen receptor administered to patients with relapsed or refractory neuroblastoma in combination with Etanercept.
研究概览
简要总结
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. We also found that a medicine called ETANercept can slow down neuroblastoma growth, which might enhance the effects of the modified cells. In this part of our study, we aim to treat children with hard-to-treat neuroblastoma using these modified NKT cells along with ETANercept. Though ETANercept has been used to treat other diseases, such as rheumatoid arthritis in children, there is limited information about the safety, efficacy, and risk of ETANercept treatment in combination with cellular therapies.
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.
详细描述
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.
Patients will be treated on a single fixed dose level with Etanercept from now on. If there is severe toxicity related to the combination of GINAKIT cells and Etanercept, we will treat patients on lower dose level. Thus maximum 36 patients will be recruited on the on the combination therapy, including 18 patients potentially at the lower dose level. If we are not able to generate sufficient GINAKIT cells on the fixed dose level, we will treat you with the highest dose level that is achieved.
Before getting the GINAKIT cells, the patient will receive cyclophosphamide and fludarabine intravenously (through a needle inserted into a vein or a port-a-cath) for 2 days and then fludarabine alone for one more day. The patient will then receive ETANercept subcutaneously (through a needle just under the skin) once per week starting the day after chemotherapy for 5 doses. The patient will receive the GINAKIT cells the day after first dose of ETANercept.
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Relapsed or refractory high risk neuroblastoma
- •Life expectancy of at least 12 weeks
- •Age greater than 1 year and less than 21 years old
- •Karnofsky/Lansky score of 60% or greater
- •Absence of HAMA prior to enrollment (only in patients that have been previously treated with murine antibodies)
- •Ability to tolerate leukocyte apheresis
- •Informed consent and assent (as applicable) obtained from parent/guardian and child.
- •Patients must have an ANC greater than or equal to 500/µl, platelet count greater than or equal to 20,000/µl. Patients may be transfused to obtain a platelet count greater than or equal to 20,000/µl.
- •Pulse Ox greater than or equal to 90% on room air
- •Serum AST less than 3 times the upper limit of normal
- •Total Bilirubin less than 1.5 times the upper limit of normal
- •Creatinine < 1.5 times the upper limit of normal
- •Recovered from the acute toxic effects of all prior chemotherapy based on the enrolling physician's assessment (if some effects of chemotherapy are expected to last long term, patient is eligible if meeting other eligibility criteria).
- •Weight greater than 12kg
- •Negative QuantiFERON-TB or T-SPOT testing within 3 months prior to procurement
- •Procurement
排除标准
- •Rapidly progressive disease
- •History or hypersensitivity to murine protein-containing products
- •Tumor causing airway obstruction
- •Currently receiving immunosuppressive drugs such as corticosteroids, tacrolimus or cyclosporine
- •Severe previous toxicity from cyclophosphamide or fludarabine based on the enrolling physician's assessment
- •HIV infection
- •History of hypersensitivity, anaphylaxis, and/or adverse event with Etanercept
- •Treatment Inclusion Criteria:
- •Relapsed or refractory high risk neuroblastoma
- •Life expectancy of at least 12 weeks
- •Age greater than 1 year and less than 21 years old
- •Karnofsky/Lansky score of 60% or greater
- •Patients must have an ANC greater than or equal to 500/µl, platelet count greater than or equal to 20,000/µl. Patients may be transfused to obtain a platelet count greater than or equal to 20,000/µl.
- •Pulse Ox greater than or equal to 90% on room air
- •Serum AST less than 3 times the upper limit of normal
- •Total Bilirubin less than 1.5 times the upper limit of normal
- •Creatinine < 1.5 times the upper limit of normal
- •Recovered from the acute toxic effects of all prior chemotherapy based on the enrolling physician's assessment (if some effects of chemotherapy are expected to last long term, patient is eligible if meeting other eligibility criteria and expected to tolerate lymphodepletion).
- •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 NKTs with greater than or equal to 20% expression of GD2-specific CAR.
- •Informed consent and assent (as applicable) obtained from parent/guardian and child.
- •Weight greater than 12kg
- •Negative QuantiFERON-TB or T-SPOT testing within 3 months prior to the start of LD
- •Treatment Exclusion Criteria:
- •Rapidly progressive disease
- •Currently receiving any investigational drugs
- •History or hypersensitivity to murine protein-containing products
- •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).
- •Tumor potentially causing airway obstruction
- •Pregnancy or lactation or not willing to use birth control
- •Currently receiving immunosuppressive drugs such as corticosteroids, tacrolimus or cyclosporine
- •Severe previous toxicity form cyclophosphamide or fludarabine based on the enrolling physician's assessment
- •HIV infection
- •History of hypersensitivity, anaphylaxis, and/or adverse event with Etanercept
研究组 & 干预措施
GINAKIT cells
GINAKIT cells will be administer to patients with Neuroblastomas on Day 0.
干预措施: GINAKIT Cells (Genetic)
Experimental: GINAKIT cells + Etanercept.
GINAKIT cells will be administer to patients with Neuroblastomas on Day 0 in combination of Etanercept.
干预措施: GINAKIT cells + Etanercept (Biological)
结局指标
主要结局
Maximum tolerated dose of autologous NKTs expressing a 2nd generation GD2-specific chimeric antigen receptor administered to patients with relapsed or refractory neuroblastoma in combination with Etanercept.
时间窗: 28 days
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 in combination with Etanercept.
次要结局
- Anti-tumor response of autologous GINAKIT cells in patients with relapsed/refractory neuroblastoma and compare the anti-tumor response in patients treated with and without Etanercept.(15 years)
研究者
Gengwen Tian, MD, PhD
Assistant Professor
Baylor College of Medicine