Administration of TGF-b Resistant LMP-Specific Cytotoxic T-Lymphocytes to Patients With Relapsed EBV-Positive Lymphoma
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 8
- 试验地点
- 2
- 主要终点
- Safety and MTD of 2 IV injections of autologous/syngeneic or allogeneic TGFb resistant LMP-specific cytotoxic T-lymphocytes.
研究概览
简要总结
Patients have a type of lymph gland cancer called HD, NHL or lymphoepithelioma (these 3 diseases will be referred to as "Lymphoma"). The lymphoma has come back or has not gone away after treatment. This is a research study using special immune system cells called TGFb-resistant LMP-specific cytotoxic T lymphocytes (DNR-CTL), a new experimental therapy.
Some patients with Lymphoma show signs of infection with the Epstein Barr virus (EBV) before or at the time of their Lymphoma diagnosis. EBV is found in the cancer cells of up to 1/2 the patients with Lymphoma, suggesting it may play a role in causing Lymphoma. The cancer cells infected by EBV are able to hide from the body's immune system and escape being killed by releasing a substance called Transforming Growth Factor-beta (TGFb). The investigators want to see if special white blood cells (called T cells) that have been given a gene that they hope will let them survive against TGFb and that have been trained to kill EBV infected cells can also survive in the blood and kill the tumor.
Investigators have used this sort of therapy with specially trained T cells to treat a different type of cancer that occurs after bone marrow and solid organ transplant called post transplant lymphoma. In this type of cancer they were able to successfully prevent and treat post transplant lymphoma. However when they used a similar approach in HD some patients had a partial response to this therapy, but no patients had a complete response. In a follow-up study they tried to find out if they could improve this treatment by growing T cells that recognize 2 of the proteins expressed on Lymphoma cells called LMP-1 and LMP2a. These special T cells were called LMP-specific cytotoxic T-lymphocytes (CTLs). Although some patients had tumor responses, CTL therapy alone did not cure those who had a lot of disease. Investigators think that a reason for this is that the tumor cells are releasing TGFb. For this reason, they want to find out if they can make the CTL resistant to TGFb by putting in a new gene called TGFb resistance gene. Investigators hope that this will improve this treatment for relapsed lymphoma. These TGFb-resistant LMP-specific CTLs are an investigational product not approved by FDA.
The purpose of this study is to find the largest safe dose of TGFb resistant LMP-specific CTLs, to learn what the side effects are and to see whether this therapy might help patients with Lymphoma.
详细描述
Investigators will test a biopsy of the tumor to see if the tumor cells are EBV positive and to see if the subject is eligible for this study. Then they will take some blood from the donor, which is used to grow T cells. First they will grow a special type of cell called dendritic cells (or monocytes), which stimulates the T cells and add a specially produced human adenovirus that carries the LMP1 and LMP-2a genes into the dendritic cells(or monocytes). Addition of a gene to the cells is known as gene transfer. These dendritic cells (or monocytes) are then used to stimulate T cells. The stimulation trains the T cells to kill cells with LMP on their surface. Investigators will then make more LMP-specific CTLs by stimulating them with EBV infected cells (which we will make from the subject's blood or the donor's blood by infecting them with EBV in the laboratory). They also will put the adenovirus that carries the LMP1 and LMP2 genes into these EBV infected cells so that they increase the amount of LMP1 and LMP2, which these cells have.
These EBV infected cells are treated with radiation so they cannot grow. Once sufficient numbers of T cells are made, investigators test them to see if they kill cells with LMP on their surface. To make sure that these cells won't attack the subjects tissues they test the cells against the skin cells or against T cells that they grow in the laboratory.
To make these CTL resistant to the effects of the TGFb released by the tumor we put in a new gene called a mutant TGFb receptor. Investigators used a mouse retrovirus that had been changed to stop it from causing infection to add the mutant TGFb receptor to the cells.
WHAT THE INFUSION WILL BE LIKE:
After the cells are made, they will be frozen. If the subject agrees to participate in this study, at the time they are scheduled to be treated, the cells will then be thawed and injected into the subject over 10 minutes.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
TGFbeta resistant LMP-specific CTLs
CTLs be given by intravenous injection over 1-10 minutes through either a peripheral or a central line.
If patients with active disease have stable disease or a partial response at their 6 week or subsequent evaluations they will be eligible to receive up to 6 additional doses of CTLs at 1-2 monthly intervals-each of which will consist of the same cell number as their second injection.
干预措施: TGFbeta resistant LMP-specific CTLs (Biological)
结局指标
主要结局
Safety and MTD of 2 IV injections of autologous/syngeneic or allogeneic TGFb resistant LMP-specific cytotoxic T-lymphocytes.
时间窗: 6 weeks
Number of patients with Dose-Limiting Toxicity (DLT).
次要结局
- Survival and immune function of TGFbeta-resistant LMP-specific cytotoxic T-lymphocytes.(15 years)
- Determine anti-viral and anti-tumor effects of TGFbeta resistant LMP-specific CTL.(15 years)
研究者
Helen Heslop
Professor
Baylor College of Medicine