Translational linkage strategies for DNA vaccines against cancer

抗癌 DNA 疫苗的转化连锁策略

基本信息

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
项目类别：
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

项目摘要

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）：该项目的目标是开发有效的分子确定的免疫佐剂，用于主动免疫癌症，并与更有效的免疫佐剂直接相关，用于针对传染性病原体的免疫。尽管对癌症的耐受性是可逆的，但针对癌症自身抗原的免疫面临着与耐受性和免疫调节相关的巨大障碍。有效的免疫佐剂对于成功地针对癌症自身抗原进行主动免疫是必要的，癌症自身抗原本身免疫原性较差。最近，我们获得的数据表明，在用基因融合佐剂免疫的动物中，适应性免疫反应的细胞被强劲激活。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））与优化的自身抗原（酪氨酸酶相关蛋白 1 = TYRP1）相结合，生成增强协同作用的融合基因产物。和高效的免疫反应。基于广泛的初步筛选以及我们对这些分子如何调节获得性免疫细胞激活的理解，编码各种候选微生物基因融合体的 DNA 是经过精心挑选的。引发免疫细胞最有效激活的微生物基因融合佐剂将被组合到单个质粒上，通过来自口蹄疫病毒（FMDV）的 18 个氨基酸“2A 序列”连接，以产生双顺反子DNA疫苗。具体目标 1 检查与单个基因融合相比，通过 2A 序列偶联的两个或多个基因融合的组合是否可以提高免疫细胞激活水平。具体目标 2 研究最有效的 2A 连锁基因融合嵌合体的 T 细胞激活机制。具体目标 3 评估多拷贝 DNA 微生物融合疫苗作为可与 IL-12/Fc 融合 DNA 构建体一起用于对抗不同肿瘤的组合制剂是否有效。