Translational linkage strategies for DNA vaccines against cancer

抗癌 DNA 疫苗的转化连锁策略

• 批准号: 7528755
• 负责人: Eric Scott Alonzo
• 金额: $ 4.1万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-26 至 2011-09-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7528755
• 关键词: Active Immunization; Address; Adjuvant; Adjuvanticity; Affect; Amino Acids; Animals; Antigens; Autoantigens; Binding; CD8B1 gene; Cells; Chimera organism; Complementary DNA; Coupled; DNA; DNA Vaccines; Data; Dendritic Cells; Enterotoxins; Escherichia coli; Exotoxins; Face; Fc Receptor; Fc domain; Foot-and-Mouth Disease Virus; Gene Fusion; Genes; Genetic; Goals; Herpesviridae; Immune; Immune Cell Activation; Immune Tolerance; Immune response; Immunity; Immunization; Immunoglobulin G; Immunologic Adjuvants; Interleukin-12; Knowledge; Ligands; Link; Major Histocompatibility Complex; Malignant Neoplasms; Memory; Molecular; Mus; Peptides; Plasmids; Play; Proteins; Pseudomonas; Pseudomonas aeruginosa toxA protein; Publishing; Regulation; Role; Screening procedure; Series; Simplexvirus; Skin; T-Cell Activation; T-Lymphocyte; TYRP1 gene; Techniques; Tumor Immunity; Tyrosinase related protein-1; Vaccines; antigen processing; base; chemokine; combinatorial; comparative; cytokine; enzyme linked immunospot assay; fusion gene; human TYRP1 protein; immunogenic; improved; in vivo; insight; microbial; migration; novel; pathogen; plasmid DNA; tumor

DESCRIPTION (provided by applicant): The goal of this project is to develop effective molecularly-defined immune adjuvants for active immunization against cancer, and with direct relevance for more potent immune adjuvants for immunization against infectious pathogens. Although tolerance to cancer is reversible, immunization against cancer self-antigens faces substantial hurdles related to tolerance and immune regulation. Potent immune adjuvants will be necessary for successful active immunization against cancer self-antigens, which are inherently poorly immunogenic. Recently, we have acquired data that demonstrates robust activation of cells from the adaptive immune response in animals immunized with gene-fusion adjuvants. We use genetic adjuvants (plasmid DNA) that combine microbial genes, including VP22 (Herpesvirus) and Exotoxin A (Pseudomonas aeruginosa), with an optimized self-antigen (tyrosinase-related protein 1 = TYRP1) to generate fusion gene products that potentiate a synergistic and highly effectual immune response. DNA encoding a variety of candidate microbial gene-fusions have been carefully selected based on extensive preliminary screening and on our understanding of how these molecules regulate the activation of acquired immune cells. The microbial gene-fusion adjuvants that elicit the most potent activation of immune cells will be combined onto a single plasmid, linked by an 18 amino acid "2A sequence" from the foot-and-mouth disease virus (FMDV), to generate a bicistronic DNA vaccine. Specific Aim 1 examines whether combining two or more gene-fusions coupled by the 2A sequence can increase the level of immune cell activation compared to a single gene-fusion. Specific Aim 2 studies the mechanism of T-cell activation from the most potent 2A-linked gene-fusion chimeras. Specific Aim 3 evaluates whether multi-copy DNA microbial fusion vaccines are effective, as combinatorial agents that can be applied with an IL-12/Fc fusion DNA construct against different tumors.

描述（由申请人提供）：该项目的目的是开发有效的分子免疫佐剂，以进行主动免疫对癌症，并与更有效的免疫辅助药物直接相关，以抗传染病。尽管对癌症的耐受性是可逆的，但对癌症自我抗原的免疫却面临着与耐受性和免疫调节有关的重大障碍。对于成功的癌症自我抗原，有效的免疫免疫是必不可少的，后者本质上是免疫原性的。最近，我们获取了数据，这些数据证明了用基因融合佐剂免疫的动物中适应性免疫反应从适应性免疫反应中强大的激活。我们使用遗传佐剂（质粒DNA），将微生物基因（包括VP22（疱疹病毒）和外毒素A（铜绿假单胞菌））与优化的自抗原（酪氨酸酶相关蛋白1 = tyrp1）以及产生高度抗性的融合产物抗性和高度抗性的效应。基于广泛的初步筛选以及我们对这些分子如何调节获得的免疫细胞激活的理解，已经仔细选择编码各种候选微生物基因 - 融合的DNA。引起最有效的免疫细胞激活的微生物基因融合佐剂将被合并到单个质粒上，并通过从脚和口腔疾病病毒（FMDV）的18个氨基酸“ 2A序列”连接，以产生生物发病型DNA疫苗。具体目标1检查与单个基因融合相比，结合由2A序列耦合的两个或多个基因 - 耦合是否可以增加免疫细胞活化的水平。具体目的2研究了最有效的2A连接基因融合嵌合体T细胞激活的机制。具体目标3评估多拷贝DNA微生物融合疫苗是否有效，因为可以用IL-12/FC融合DNA构建体应用于不同肿瘤的组合剂。