An Open-label Study of the Safety and Efficacy of Tag-7 Gene-modified Tumor Cell-based Vaccine in Patients With Locally Advanced or Metastatic Malignant Melanoma or Renal Cell Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 80
- 试验地点
- 1
- 主要终点
- Adverse events rate
研究概览
简要总结
This study was designed to assess the safety and efficacy of inactivated tumor cells genetically modified with the TAG-7 gene as immunotherapy for cancer. Patients with melanoma or kidney cancer were included since they have immune-dependent tumors. Treatment was done in the adjuvant setting after complete cytoreduction of locally advanced or metastatic disease or in the therapeutic setting in patients where complete cytoreduction was impossible.
详细描述
During the last decade, novel approaches for cancer treatment have been developed. Antitumor vaccines are one of the most promising approaches in tumor immunotherapy. Tumor cells possess low immunogenicity properties due to a number of the not completely understood mechanisms of resistance. One of the ways to overcome it is immune genes transfection. Genes encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-2 and IL-12 have been used most commonly, both in preclinical studies and clinical trials. These cytokines are well known to participate in the systemic immune response. Several studies have shown that the professional antigen-presenting cells (APCs) of the host, rather than the vaccinating tumor cells themselves, are responsible for priming CD4+ and CD8+ T cells, both of which are required to generate systemic antitumor immunity. Recent findings indicate that the adaptive arm of immunity is governed by the innate immune mechanisms that control the co-stimulatory signaling of APCs. Recently, investigators identified a novel gene, tag7, also know as PGRP-S. The insect ortholog of the tag7/PGRP-S was shown to be involved in the innate immune response in Drosophila. In preclinical studies, tag7-modified mouse tumor cells induced a long-lasting T-cell dependent immune response in mice. The effectiveness of antitumor vaccination was demonstrated on different models of mouse tumors, particularly for melanoma cells (M3, B16, F10). Clinically important results of vaccine therapy were achieved in patients with melanoma and renal carcinoma in a number of studies. The results with this treatment are comparable to chemotherapy and immunotherapy. Investigators assume that one has to activate the innate component of immunity first, followed by the activation of the adaptive one, to make anticancer vaccines more effective. Thus, a phase I/II clinical trial has been performed to evaluate the feasibility and toxicity of treatment with autologous tumor cells modified with the tag7 gene, which has been shown to be involved in innate immunity mechanisms,
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Signed inform consent form.
- •Patients age ≥ 18 years of age at the time of informed consent.
- •Ability to provide and understand written informed consent prior to any study procedures.
- •Histologically confirmed locally advanced or metastatic MM or RCC.
- •Tumor cell culture should be obtained and successfully transfected before inclusion.
- •No evaluable therapy with a proved survival advantage in the current patient setting.
- •The life expectancy of > 3 months as estimated by the investigator
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 -2 at Screening.
排除标准
- •Patient with any out-of-range laboratory values defined as:
- •Serum creatinine > 1.5 × upper limit of normal (ULN) and/or creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 50 mL/minute
- •Total bilirubin > 2.5 × ULN, except for patients with Gilbert's syndrome who are excluded if total bilirubin > 3.0 × ULN or direct bilirubin > 1.5 × ULN
- •Alanine aminotransferase > 2.5 × ULN
- •Aspartate aminotransferase > 2.5 × ULN
- •Absolute neutrophil count < 1.5 × 109/L
- •Platelet count < 100 × 109/L
- •Hemoglobin < 80 g/L (blood transfusions permitted)
- •History of severe hypersensitivity reactions (eg, anaphylaxis) to other biologic drugs or monoclonal antibodies
- •Any clinically significant unstable disease
- •Presence of symptomatic or untreated central nervous system (CNS) metastases
- •Active infection requiring systemic antibiotic therapy. Patients requiring systemic antibiotics for infection must have completed therapy at least 1 week prior to the first dose of study drug
- •Known history of human immunodeficiency virus infection (HIV). Testing for HIV status is not necessary unless clinically indicated
- •Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection per institutional protocol. Testing for HBV or HCV status is not necessary unless clinically indicated or the patient has a history of HBV or HCV infection
- •Malignant disease, other than that being treated in this study
- •Patients receiving systemic steroid therapy or any other systemic immunosuppressive medication at any dose level, as these may interfere with the mechanism of action of study treatment. Local steroid therapies (eg, otic, ophthalmic, intra-articular or inhaled medications) are acceptable
- •Pregnant, likely to become pregnant, or lactating women (where pregnancy is defined as the state of a female after conception and until the termination of gestation)
研究组 & 干预措施
Melanoma Adjuvant
Patients with completely resected stage III or IV melanoma receiving GMV in the adjuvant setting
干预措施: Tag-7 gene modified inactivated tumor cells (Biological)
Melanoma Therapeutic
Patients with incompletely resected stage III or IV melanoma receiving GMV in the therapeutic setting
干预措施: Tag-7 gene modified inactivated tumor cells (Biological)
Renal Cell Adjuvant
Patients with completely resected stage III or IV kidney cancer receiving GMV in the adjuvant setting
干预措施: Tag-7 gene modified inactivated tumor cells (Biological)
Renal Cell Therapeutic
Patients with incompletely resected stage III or IV kidney cancer receiving GMV in the therapeutic setting
干预措施: Tag-7 gene modified inactivated tumor cells (Biological)
结局指标
主要结局
Adverse events rate
时间窗: From the fist injection to 3 month after the last injection
CTC AE v.3 was used for safety assesment
次要结局
- Response rate(every 8 weeks until disease progression or therapy completion, then every 3 month for 2 years, every 6 month for the next 2 years and annually thereafter)
- Concentration of MICA in patient's cultures supernatants(Samples obtained before therapy start)
- Concentration of TGF-β1 in patient's cultures supernatants(Samples obtained before therapy start)
- Concentration of IL-10 in patient's cultures supernatants(Samples obtained before therapy start)
- Concentration of VEGF in patient's cultures supernatants(Samples obtained before therapy start)
- Number of T-cells in peripheral blood of patients(1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks))
- Number of Cytotoxic lymphocytes in peripheral blood of patients(1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks))
- Number of NK-lymphocytes in peripheral blood of patients(1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks))
- Number of CD38+ cells in peripheral blood of patients(1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks))
- IgA level(1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks))
- IgM level(1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks))
- Number of HLA-DR+ cells in peripheral blood of patients(1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks))
- Number of B-lymphocytes cells in peripheral blood of patients(1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks))
- Number of CD25+ cells in peripheral blood of patients(1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks))
- Kon-A stimulated migration(1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks))
- Ingestion rate of neutrophils(1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks))
- Circulating immune complex level(1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks))
- Number of T-helper lympocytes in peripheral blood of patients(1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks))
- Spontaneous lymphocytes migration(1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks))
- PGA stimulated migration(1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks))
- Number of CD71+ cells in peripheral blood of patients(1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks))
- IgG level(1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks))
- Ingestion rate of monocytes(1-5 days before each therapy cycle during course of therapy (cycle 21 days) through therapy completion, an average of 6 cycles (18 weeks))