DNA VACCINATION WITH ALTERED ANTIGENS

使用改变的抗原进行 DNA 疫苗接种

• 批准号: 6423089
• 负责人: ALAN N. HOUGHTON
• 金额: $ 29.18万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-21 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6423089
• 关键词: clinical research; clinical trial phase I; colony stimulating factor; cytotoxic T lymphocyte; differentiation antigens; glycoproteins; helper T lymphocyte; human subject; human therapy evaluation; immune tolerance /unresponsiveness; major histocompatibility complex; melanoma; metastasis; monophenol monooxygenase; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; protein signal sequence; tumor antigens; vector vaccine

The differentiation antigens have emerged as targets for cancer therapy. We will investigate DNA vaccines that are designed to break tolerance and enhance potency of immunization against melanoma differentiation Melanoma differentiation antigens will be targeted, including tyrosine, gp75TRP-1, TRP-2 and gp100. These antigens cover early and late stages of melanocyte/melanoma differentiation and are specifically selected to overcome tumor heterogeneity. These differentiation antigens are recognized by antibodies and both CD4+ and CD4+ T cells of patients with melanoma. This raises the possibility that vaccines can be designed that general humoral and cellular responses, including helper and cytotoxic T cells. Our results in laboratory models show that both antibody and T cells responses can be induced against tumor differentiation antigens by DNA immunization, but genes encoding altered antigens are required. for effective immunity. Because differentiation antigens are self antigens that are likely to be weakly immunogenic, we will investigate and compare three approaches of DNA vaccination to enhance immunogenicity and/or overcoming immune tolerance: 1. Immunization with xenogeneic DNA; 2. Immunization with DNA encoding antigens that sort to antigen presenting compartments; 3. Immunization with DNA minigenes encoding heteroclitic peptides, and 4. Augmentation of immunity by GM-CSF DNA. We expect that these approaches will lead to development of DNA vaccine of antigens of melanoma.

分化抗原已成为癌症治疗的靶标。我们将研究旨在打破耐受性并增强针对黑色素瘤分化的免疫效力的 DNA 疫苗。黑色素瘤分化抗原将成为目标，包括酪氨酸、gp75TRP-1、TRP-2 和 gp100。这些抗原涵盖黑色素细胞/黑色素瘤分化的早期和晚期阶段，并且经过专门选择以克服肿瘤异质性。这些分化抗原被黑色素瘤患者的抗体以及 CD4+ 和 CD4+ T 细胞识别。这提出了一种可能性，即可以设计出针对一般体液和细胞反应（包括辅助性 T 细胞和细胞毒性 T 细胞）的疫苗。我们在实验室模型中的结果表明，可以通过 DNA 免疫诱导抗体和 T 细胞针对肿瘤分化抗原的反应，但需要编码改变的抗原的基因。以达到有效的免疫力。由于分化抗原是自身抗原，可能具有弱免疫原性，因此我们将研究和比较三种 DNA 疫苗接种方法，以增强免疫原性和/或克服免疫耐受： 1. 异种 DNA 免疫； 2.用编码抗原的DNA进行免疫，所述抗原分选至抗原呈递区室； 3.用编码异连接肽的DNA小基因进行免疫，以及4.用GM-CSF DNA增强免疫力。我们预计这些方法将促进黑色素瘤抗原 DNA 疫苗的开发。