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。我们将研究旨在破坏耐受性和增强对黑色素瘤分化黑色素瘤分化抗原的免疫效力的DNA疫苗，包括酪氨酸，GP75TRP-1，TRP-2和GP100。这些抗原涵盖了黑色素/黑色素瘤分化的早期和晚期，并专门选择以克服肿瘤异质性。这些分化抗原均由黑色素瘤患者的抗体以及CD4+和CD4+ T细胞识别。这增加了可以设计疫苗的可能性，包括一般的体液和细胞反应，包括助手和细胞毒性T细胞。我们在实验室模型中的结果表明，抗体和T细胞反应都可以通过DNA免疫来诱导肿瘤分化抗原，但是需要编码改变的抗原的基因。为了有效的免疫力。由于分化抗原是可能具有弱免疫原性的自我抗原，因此我们将研究并比较DNA疫苗接种的三种方法，以增强免疫原性和/或克服免疫耐受性：1。用异种DNA进行免疫。 2。用编码抗原的DNA免疫，这些抗原排序抗原呈现区室； 3。用编码杂志肽的DNA微基免疫，4。通过GM-CSF DNA对免疫的增强。我们预计这些方法将导致黑色素瘤抗原DNA疫苗的发展。