Randomized Phase II Evaluation of Immunization Against Tumor Cells in Subjects With Metastatic Melanoma Using Autologous Mature Dendritic Cells
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 16
- 试验地点
- 2
- 主要终点
- Delayed Type Hypersensitivity (DTH) Response
研究概览
简要总结
The purpose of this study is to determine what effect using an experimental tumor vaccine (a substance or group of substances meant to cause the immune system to respond to a tumor) made using patients' own tumor cells and blood cells will have on their melanoma.
详细描述
Historically, metastatic melanoma has been associated with a poor prognosis. Recently, numerous immunotherapeutic agents, particularly checkpoint inhibitors, have moved to the forefront of therapy. Checkpoint inhibitors such as ipilimumab, pembrolizumab, and nivolumab have revolutionized the treatment of melanoma. Despite this, not all patients respond to checkpoint inhibitors, and even patients who initially respond to checkpoint inhibitor therapy often later relapse (median response duration of 2 years); complete responses remain uncommon. Thus, more effective immunotherapies are clearly needed.
The concept of administering dendritic cell (DC)-based vaccines to prompt an immune response against tumor cells has shown promise in the treatment of advanced cancers. Sipuleucel-T, now FDA-approved for the treatment of advanced prostate cancer, is one such vaccine that consists of autologous antigen-presenting cell (APC) activated ex vivo by a fusion protein consisting of the antigen prostatic acid phosphatase (PAP) and granulocyte-macrophage colony stimulating factor (GM-CSF). Although response rates to Sipuleucel-T are low, recent studies suggest that DC vaccines have the potential to improve survival by increasing the breadth and diversity of melanoma-specific T cells.
It is known that the method of antigen (Ag) delivery is important for the success of DC vaccines, but it remains unclear which method is most effective in producing antitumor responses. Approaches tested clinically include pulsing with HLA-restricted defined peptide Ags, loading with purified proteins, transfecting with mRNA, engineering with Ag-encoding viral vectors, and using autologous tumor cells or allogeneic cell lines directly as sources of Ag. Efficacy can be measured in vivo using surrogate endpoints, such as development of tumor-specific delayed-type hypersensitivity (DTH) reactions. Prolonged survival of vaccinated melanoma patients has been reported to correlate with induction of positive DTH tests. Antitumor activity may also be assessed by ELISpot analysis of the frequency of tumor-Ag specific IFNγ-producing T cells. To assess the quality of the DC vaccines, surrogate markers of DC function including maturation markers, co-stimulatory molecule expression, and IL12p70 production, a critical cytokine in antitumor response, can be measured
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •Subjects must have Stage III-IV melanoma (any tumor thickness and any number of lymph node involvement, and in-transit metastases, or distant metastases) (AJCC). Each diagnosis will be confirmed by pathology review at the Melanoma Center of the University of Pittsburgh Cancer Institute.
- •All subjects have to be HLA-A2 positive (required for immunologic testing).
- •Subjects must have recovered fully from surgery.
- •Availability of resectable or tissue banked tumor cells for autologous tumor dendritic cell vaccine preparation.
- •Sufficient number of tumor cells available for autologous tumor dendritic cell vaccine preparation (min 2.6 x 10 7).
- •Sufficient number of DCs of at least 12 X 10 6 for preparation of the autologous tumor dendritic cell vaccine preparation (if less than needed number of cells will be obtained by one course of leukopheresis, the second leukopheresis will be repeated 2 weeks apart).
- •Subjects must not have received any chemotherapy or immunotherapy within the four weeks preceding vaccination (six weeks for nitrosourea, mitomycin).
- •Subjects must have an expected survival of greater than or equal to 12 months.
- •Subjects must have an ECOG performance status 0 or
- •Subjects must have the following initial and subsequent pretreatment
- •laboratory parameters: Granulocytes >=2,500/mm3 Lymphocytes >=1000/mm3 Platelets >100,000/mm3 Serum Creatinine <=1.5 X the ULN AST, ALT, GGT, LDH, Alk phos <= 2.5 X the ULN Serum Bilirubin <=1.5 X ULN
- •Subjects must be >= 18 years of age and must be able to understand the written informed consent.
- •No evidence of active infection, regardless of the degree of severity or localization. Subjects with active infections (whether or not they require antibiotic therapy) may be eligible after complete resolution of the infection. Subjects on antibiotic therapy must be off antibiotics for at least 7 days before beginning treatment.
- •Subjects with measurable disease must have an evaluation for extent of disease (tumor staging) performed within 30 days of start of treatment.
- •Pretreatment baseline evaluations for laboratory parameters must be obtained within 10 to18 days of subject registration
排除标准
- •Subjects currently treated with anti inflammatory agents including glucocorticoid therapy are ineligible.
- •Subjects currently on treatment with steroids are ineligible, but may receive the DC autologous tumor dendritic cell vaccine 4 weeks after steroid cessation. Subjects on maintenance steroids because of adrenal insufficiency are eligible.
- •Subjects with severely abnormal liver function tests [AST (SGOT), ALT (SGPT), GGT, Alk.Phos, LDH, and total bilirubin greater than 2 X ULN].
- •Subjects with uncontrolled pain.
- •Subjects with autoimmune disease, HIV, and hepatitis
- •Subjects with symptomatic brain metastasis.
- •Subjects with active prior malignancy (with exception of non-melanoma skin cancers and carcinoma in situ of the cervix).
- •Subjects who have been previously immunized with melanoma vaccine until 10 subjects have been registered in each treatment arm.
- •Subjects who are pregnant.
- •Subjects who have sensitivity to drugs to provide local anesthesia.
研究组 & 干预措施
Vaccine co-cultured with melanoma cells
Dendritic Cells co-cultured with melanoma cells injected as a vaccine intra/peri-nodally under ultrasound guidance
干预措施: Vaccination (Biological)
Vaccine pulsed with tumor cell lysates
Dendritic Cells pulsed with tumor cell lysates were injected as a vaccine intra/peri-nodally under ultrasound guidance
干预措施: Vaccination (Biological)
Vaccine fused with tumor cells
Dendritic Cells fused with tumor cells were injected as a vaccine intra/peri-nodally under ultrasound guidance
干预措施: Vaccination (Biological)
结局指标
主要结局
Delayed Type Hypersensitivity (DTH) Response
时间窗: 12 mo
Delayed type hypersensitivity (DTH) response to antigen-loaded autologous, dendritic cell vaccine (DC) injected intradermal in vivo
ELISpot Response to Melanoma
时间窗: 12 mo
Peripheral blood CD8+ and CD4+ T cell responses against autologous tumor cells, and HLA-presented melanoma epitopes, using ELISPOT and MHC-peptide tetramer assays.
次要结局
未报告次要终点