Phase II Study of Metastatic Melanoma Using Lymphodepleting Conditioning Followed by Infusion of Anti-MART-1 F5 TCR-Gene Engineered Lymphocytes and ALVAC Virus Immunization
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 4
- 试验地点
- 1
- 主要终点
- Number of Participants With Metastatic Melanoma Who Develop Clinical Tumor Regression (CR or PR)
研究概览
简要总结
Background:
- Melanoma antigen recognized by T-cells (MART)-1 is a protein present in melanoma cells.
- An experimental procedure developed for treating patients with melanoma uses the anti-MART-1 F5 gene and a type of virus to make special cells called anti-MART-1 F5 cells that are designed to destroy the patient's tumor. These cells are created in the laboratory using the patient's own tumor cells or blood cells.
- The treatment procedure also uses a vaccine called plaque purified canarypox vector (ALVAC) MART-1, made from a virus that ordinarily infects canaries and is modified to carry a copy of the MART-1 gene. The virus cannot reproduce in mammals, so it cannot cause disease in humans. When the vaccine is injected into a patient, it stimulates cells in the immune system that may increase the efficiency of the anti-MART-1 F5 cells.
Objectives:
-To evaluate the safety and effectiveness of anti-MART-1 F5 and the ALVAC vaccine in treating patients with advanced melanoma.
Eligibility:
-Patients 18 years of age with metastatic melanoma for whom standard treatments have not been effective.
Design:
- Patients undergo scans, x-rays and other tests and leukapheresis to obtain white cells for laboratory treatment.
- Patients have 7 days of chemotherapy to prepare the immune system for receiving the anti-MART-1 F5.
- Patients receive the ALVAC vaccine, anti-MART-1 F5 cells and interleukin-2 (IL-2) (an approved treatment for advanced melanoma). The anti-MART-1 F5 cells are given as an infusion through a vein. The vaccine is given as injections just before the infusion of anti-MART-1 F5 cells and again 2 weeks later. IL-2 is given as a 15-minute infusion every 8 hours for up to 5 days after the cell infusion for a maximum of 15 doses.
- After hospital discharge, patients return to the clinic for periodic follow-up with a physical examination, review of treatment side effects, laboratory tests and scans every 1 to 6 months.
详细描述
Background:
- We have engineered human PBLs to express an anti-MART-1 T-cell receptor that recognizes an human leukocyte antigens (HLA-A) 0201 restricted epitope derived from the tumor infiltrating lymphocytes (TIL) clone DMF5.
- We constructed a single retroviral vector that contains both alpha and infinity chains and can mediate genetic transfer of this T cell receptor (TCR) with high efficiency without the need to perform any selection.
- In co-cultures with HLA-A 0201 positive melanoma, anti-MART-1 F5 TCR transduced T cells secreted significant amount of interferon (IFN)-(but no significant secretion was observed in control co-cultures with cell lines.
- The anti-MART-1 F5 TCR transduced peripheral blood lymphocytes (PBL) could efficiently kill HLA-A 0201 positive tumors. There was little or no recognition of normal fibroblasts cells.
- This TCR is over 10 times more reactive with melanoma cells than the MART-1 TCR that mediated tumor regression in two patients with metastatic melanoma.
- In this trial we would like to test our hypothesis that the addition of an anti-tumor ALVAC vaccine will result in clinical tumor regression and persistence of the transferred cells (as is the case in murine models).
Objectives:
Primary objectives:
-Determine if the administration of anti-MART-1 F5 TCR -engineered peripheral blood lymphocytes, ALVAC anti-tumor immunization, and aldesleukin to patients following a nonmyeloablative but lymphoid depleting preparative regimen will result in clinical tumor regression in patients with metastatic melanoma.
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
- 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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
ALVAC plus anti-MART-1 F5 TCR PBL + HD IL-2
ALVAC plus anti-MART-1 F5 T cell receptor (TCR ) peripheral blood lymphocytes (PBL) + high dose (HD) interleukin 2 (IL-2): ALVAC vaccine-approximately two hours prior to cell infusion, patients will receive 0.5 mL containing a target dose of 10^7 cell culture infectious dose 50% (CCID50) (with a range of approximately 10^6,4 to 10^7,9/mL) of the MART-1 ALVAC virus subcutaneously in each extremity (total of 4 x 10^7 CCID50/2 mL). This will be repeated on day 14.
Aldesleukin - 720,000 IU/kg intravenously over 15 minutes every 8 hours (+/- 1 hour) for up to 5 days.
干预措施: autologous anti-MART-1 F5 T-cell receptor gene-engineered peripheral blood lymphocytes (Biological)
ALVAC plus anti-MART-1 F5 TCR PBL + HD IL-2
ALVAC plus anti-MART-1 F5 T cell receptor (TCR ) peripheral blood lymphocytes (PBL) + high dose (HD) interleukin 2 (IL-2): ALVAC vaccine-approximately two hours prior to cell infusion, patients will receive 0.5 mL containing a target dose of 10^7 cell culture infectious dose 50% (CCID50) (with a range of approximately 10^6,4 to 10^7,9/mL) of the MART-1 ALVAC virus subcutaneously in each extremity (total of 4 x 10^7 CCID50/2 mL). This will be repeated on day 14.
Aldesleukin - 720,000 IU/kg intravenously over 15 minutes every 8 hours (+/- 1 hour) for up to 5 days.
干预措施: ALVAC MART-1 Vaccine (Biological)
ALVAC plus anti-MART-1 F5 TCR PBL + HD IL-2
ALVAC plus anti-MART-1 F5 T cell receptor (TCR ) peripheral blood lymphocytes (PBL) + high dose (HD) interleukin 2 (IL-2): ALVAC vaccine-approximately two hours prior to cell infusion, patients will receive 0.5 mL containing a target dose of 10^7 cell culture infectious dose 50% (CCID50) (with a range of approximately 10^6,4 to 10^7,9/mL) of the MART-1 ALVAC virus subcutaneously in each extremity (total of 4 x 10^7 CCID50/2 mL). This will be repeated on day 14.
Aldesleukin - 720,000 IU/kg intravenously over 15 minutes every 8 hours (+/- 1 hour) for up to 5 days.
干预措施: aldesleukin (Biological)
ALVAC plus anti-MART-1 F5 TCR PBL + HD IL-2
ALVAC plus anti-MART-1 F5 T cell receptor (TCR ) peripheral blood lymphocytes (PBL) + high dose (HD) interleukin 2 (IL-2): ALVAC vaccine-approximately two hours prior to cell infusion, patients will receive 0.5 mL containing a target dose of 10^7 cell culture infectious dose 50% (CCID50) (with a range of approximately 10^6,4 to 10^7,9/mL) of the MART-1 ALVAC virus subcutaneously in each extremity (total of 4 x 10^7 CCID50/2 mL). This will be repeated on day 14.
Aldesleukin - 720,000 IU/kg intravenously over 15 minutes every 8 hours (+/- 1 hour) for up to 5 days.
干预措施: cyclophosphamide (Drug)
ALVAC plus anti-MART-1 F5 TCR PBL + HD IL-2
ALVAC plus anti-MART-1 F5 T cell receptor (TCR ) peripheral blood lymphocytes (PBL) + high dose (HD) interleukin 2 (IL-2): ALVAC vaccine-approximately two hours prior to cell infusion, patients will receive 0.5 mL containing a target dose of 10^7 cell culture infectious dose 50% (CCID50) (with a range of approximately 10^6,4 to 10^7,9/mL) of the MART-1 ALVAC virus subcutaneously in each extremity (total of 4 x 10^7 CCID50/2 mL). This will be repeated on day 14.
Aldesleukin - 720,000 IU/kg intravenously over 15 minutes every 8 hours (+/- 1 hour) for up to 5 days.
干预措施: fludarabine phosphate (Drug)
结局指标
主要结局
Number of Participants With Metastatic Melanoma Who Develop Clinical Tumor Regression (CR or PR)
时间窗: 4-6 weeks after treatment and then monthly for approximately 3 to 4 months or until off study criteria are met
Clinical tumor response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.0 criteria. Complete response (CR) is a disappearance of all target lesions. Partial response (PR) is a 30% decrease in lesions taking as reference the baseline sum longest diameter (LD). For details about the RECIST criteria see the protocol link module.
次要结局
- Number of Participants With in Vivo Survival of T-cell Receptor (TCR) Gene-engineered Cells(1 month)
- Number of Participants With Adverse Events(15 months)
研究者
Steven Rosenberg, M.D.
Principal Investigator
National Institutes of Health Clinical Center (CC)