HPV-16/18 E6/E7-Specific T Lymphocytes in Patients With Relapsed HPV-Associated Cancers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 32
- 试验地点
- 2
- 主要终点
- Number of patients with dose limiting toxicity (DLT)
研究概览
简要总结
Subjects have a type of cancer that has been associated with an infection with a virus called human papilloma virus (HPV). The cancer has come back, has not gone away after standard treatment or the subject cannot receive standard treatment.
This is a research study using special immune system cells called HPVST cells, a new experimental treatment.
Investigators want to find out if they can use this type of treatment in patients with HPV-cancers. They have discovered a way to grow large number of HPV-specific T cells from the blood of patients with HPV-cancers. They want to see if these special white blood cells, called HPVST cells, that will have been trained to kill HPV infected cells can survive in the blood and affect the tumor. They will also see if they can make the T cells more active against the HPV-cancers by engineering them to be resistant to the TGF-beta chemical that these HPV-cancers produce. They will grow these HPVST cells from the patient's blood.
The purpose of this study is to find the biggest dose of HPVSTs that is safe, to see how long they last in the body, to learn what the side effects are and to see if the HPVSTs will help people with HPV associated cancers.
If the treatment with HPVST cells alone proves safe (Group A), additional group of patients (Group B) will receive Nivolumab in addition to HPVST cells in a lymphodepleted environment. Nivolumab is an antibody therapy that helps T cells control the tumor and it is FDA approved for the treatment of certain types of cancers, including Hodgkin's lymphoma. Lymphodepletion will decrease the level of circulating T cells prior to infusion of HPVST cells, thereby giving them room to expand. The purpose of this part of the study is to find out if TGF-beta resistant HPVST cells in combination with Nivolumab are safe, how long they last in the body and if they are more effective than HPVST cells alone in controlling the tumor.
详细描述
HPV is found in the cancer cells of more than half the patients with certain types of cancer, suggesting that it may play a role in causing the cancer. The virus makes proteins in the tumor cells that should allow the diseased cells to be recognized and killed by a part of the body's own immune system called T cells. Unfortunately, tumors are able to avoid being killed by making molecules that turn off these T cells. So, the cancer cells infected by HPV are able to hide from the body's immune system and escape destruction.
The investigators have previously studied cancers caused by a different virus, called Epstein-Barr virus (EBV). These EBV-cancers are like HPV-cancers, since they turn off the T cells that would otherwise destroy them, and so can keep growing. They investigators have found, however, that if they removed the T cells from the blood of patients with EBV-cancers and grew them outside the body, they could increase the number and the activity of T cells directed against the tumors. When these T cells were given back to the patients, the T cells eliminated the cancers in over half the recipients. Investigators also found that they could engineer the T cells to be even more active against the EBV-cancer cells by making them resist an inhibitory chemical called TGF-beta, which is produced by these cancer cells.
Investigators will collect up to 390 mL of blood. Then they will use this blood to grow T cells. First they will grow them in a special type of cell called a dendritic cell, which stimulates the T cells. These dendritic cells will then be loaded with bits of proteins from the HPV virus called E6 and E7. These dendritic cells will be used to stimulate T cells. This stimulation trains the T cells to kill cells with the HPV proteins E6 and E7 on their surface. Next, the investigators will grow these HPV-specific T cells by more stimulation with dendritic cells and HPV proteins, and, when needed, a special type of cell called K562. These K562 cells were treated with radiation so they cannot grow.
To make these T cells resistant to the TGF-beta released by the tumor, investigators will put a new gene in them in the laboratory called a mutant TGF-beta receptor. In cells with this new gene, TGF-beta released by the tumor cells will not be able to bind to the mutant TGF-beta receptor on the T cell. Investigators hope this will improve the chances that after the T cells are injected they will be able to keep working and kill the tumor cells. This gene is added to the cells using a mouse retrovirus that has been changed to stop it from causing infections. Retroviruses enter the cell's DNA (genetic material) to make permanent changes to the cell. After making these cells, they will be frozen.
For treatment, the cells will be thawed and injected in a vein over 1 to 10 minutes. Initially, one dose of T cells will be given (which is considered day 0).
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
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •PROCUREMENT
- •Diagnosis of a cancer for which the presence of a high risk HPV type has been documented in a biopsy sample
- •recurrent or persistent after standard therapy
- •OR patient is unable to receive standard therapy
- •Karnofsky score ≥ 50%
- •Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent
- •Diagnosis of a cancer for which the presence of a high risk HPV type has been documented in a biopsy sample
- •recurrent or persistent after standard therapy
- •OR patient is unable to receive standard therapy
- •Life expectancy ≥ 6 weeks.
- •Age ≥ 18 years.
- •Karnofsky score ≥ 50%
- •Bilirubin < 3 × upper limit of normal (ULN), AST < 5 × ULN, Hgb ≥ 7.0 g/dL
- •Pulse oximetry of > 90% on room air.
- •GFR > 30 mL/min calculated by the Cockcroft-Gault, MDRD study, or CKD-EPI creatinine equations, or equivalent.
- •ANC > 1.0/μL
- •Platelets > 75,000/μL
- •Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent
- •Sexually active patients must be willing to utilize one of the more effective birth control methods during the study and for 6 months after the study is concluded. The male partner should use a condom.
排除标准
- •PROCUREMENT
- •1. Known HIV positivity.
- •Currently receiving any investigational agents or have received any tumor vaccines or T cell antibodies within previous 4 weeks.
- •Severe intercurrent infection.
- •Pregnancy or lactation.
研究组 & 干预措施
Group B
HPV Specific T Cells plus lymphodepletion (Cytoxan and Fludarabine) and nivolumab
干预措施: Nivolumab (Biological)
Group B
HPV Specific T Cells plus lymphodepletion (Cytoxan and Fludarabine) and nivolumab
干预措施: Cytoxan (Drug)
Group A
HPV Specific T Cells
干预措施: HPV Specific T Cells (Genetic)
Group B
HPV Specific T Cells plus lymphodepletion (Cytoxan and Fludarabine) and nivolumab
干预措施: HPV Specific T Cells (Genetic)
Group B
HPV Specific T Cells plus lymphodepletion (Cytoxan and Fludarabine) and nivolumab
干预措施: Fludarabine (Drug)
结局指标
主要结局
Number of patients with dose limiting toxicity (DLT)
时间窗: 6 weeks
DLT will be defined as any toxicity that is irreversible or life threatening, defined as the following, considered to be possibly, probably, or definitely related to the HPVST injection. 1. Non-hematologic DLT is any grade 3 or grade 4 non-hematologic toxicity. 2. Hematologic DLT is defined as any grade 4 hematologic toxicity.
次要结局
- Overall response rate(6 weeks)
研究者
Carlos Ramos
Assistant Professor
Baylor College of Medicine