Genetic Approaches to Immune Adjuvants

免疫佐剂的遗传学方法

• 批准号: 7136185
• 负责人: ALAN N. HOUGHTON
• 金额: $ 16.39万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7136185
• 关键词: DNA; active immunization; antigens; cytokine; genetics; melanoma; neoplasm /cancer

The goal of this project is to develop effective molecularly-defined immune adjuvants for active immunization against cancer. Although tolerance to cancer is reversible, immunization against cancer antigens faces substantial hurdles related to tolerance and immune regulation. Potent immune adjuvants will be necessary for successful active immunization against cancer antigens, which are inherently poorly immunogenic. We apply recent knowledge about molecules that regulate growth, activation and survival of innate and acquired immune cells to study adjuvant strategies and underlying mechanisms. We use genetic adjuvants (plasmid DNA incorporating Fc domains of IgG) combined with DNA vaccines against cancer antigens. DNA encoding cytokines have been carefully selected for analysis based on results of extensive preliminary screening and on our understanding about how these molecules regulate activation and survival of innate and acquired immune cells. Specific aim 1 is built on experimental results from our screens showing that DNA encoding an IL-12/Fc fusion molecule is most effective at enhancing T cell responses and tumor immunity. A phase I clinical trial is proposed to assess safety of IL-12/Fc DNA and compare the relative immunologic efficacy of vaccination with tyrosinase DNA plus IL-12/Fc DNA adjuvant to tyrosinase DNA alone in patients with stage III melanoma. Specific aim 2 examines why ligation of Fc domains to cytokines markedly increases adjuvanticity while unexpectedly decreasing their bioavailability. Genetic approaches are used to address the hypothesis that adjuvant effects are amplified by interactions with Fc receptors on innate immune cells. Specific aim 3 studies DNA adjuvants combined with vaccination in treatment models of melanoma, including treatment in a transgenic model that develops de novo melanoma. Subaims investigate a) the role of IFNgamma produced by NK cells for adjuvanticity by cytokine and cytokine/Fc cDNAs, and b) adjuvant effects of IL-23 DNA, which is strongly implicated in the pathogenesis of inflammatory autoimmune diseases. Specific aim 4 investigates the role of cytokine DNA adjuvants for potentiating antigen-specific responses elicited by vaccination during homeostatic recovery of the immune system after non-myeloablative treatments. The overall goal is to develop the most potent DNA adjuvants that can be applied to vaccines delivered during homeostatic recovery.

该项目的目标是开发有效的分子限定免疫佐剂用于主动免疫 对抗癌症。尽管对癌症的耐受是可逆的，但针对癌症抗原的免疫仍面临着挑战。 与耐受性和免疫调节相关的重大障碍。需要有效的免疫佐剂 成功地针对癌症抗原进行主动免疫，癌症抗原本质上免疫原性较差。我们 应用有关调节先天和后天生长、激活和生存的分子的最新知识 免疫细胞研究佐剂策略和潜在机制。我们使用遗传佐剂（质粒 结合 IgG Fc 结构域的 DNA 与针对癌症抗原的 DNA 疫苗相结合。脱氧核糖核酸 根据广泛的初步结果，精心选择编码细胞因子进行分析 筛选以及我们对这些分子如何调节先天细胞的激活和生存的理解 并获得了免疫细胞。具体目标 1 基于我们屏幕上的实验结果，表明 编码 IL-12/Fc 融合分子的 DNA 在增强 T 细胞反应和肿瘤治疗方面最有效 免疫。拟开展 I 期临床试验来评估 IL-12/Fc DNA 的安全性并比较相对值 酪氨酸酶 DNA 加 IL-12/Fc DNA 酪氨酸酶 DNA 佐剂疫苗接种的免疫效果 单独用于 III 期黑色素瘤患者。具体目标 2 研究为什么 Fc 结构域与细胞因子连接 显着增加佐剂作用，同时意外地降低其生物利用度。遗传方法 用于解决佐剂效应通过与 Fc 受体相互作用而放大的假设 先天免疫细胞。具体目标 3 研究 DNA 佐剂联合疫苗接种的治疗模型 黑色素瘤的治疗，包括在从头发展黑色素瘤的转基因模型中进行治疗。苏拜姆斯 研究a) NK细胞产生的IFNγ对于细胞因子和细胞因子/Fc cDNA的佐剂作用的作用， b) IL-23 DNA 的佐剂作用，与炎症的发病机制密切相关 自身免疫性疾病。具体目标 4 研究细胞因子 DNA 佐剂的增强作用 疫苗接种后免疫系统稳态恢复过程中引起的抗原特异性反应 非清髓性治疗。总体目标是开发最有效的 DNA 佐剂 适用于稳态恢复期间递送的疫苗。