Exploiting the Unique T Cell Response to CMV for a Cancer Vaccine

利用 T 细胞对 CMV 的独特反应来开发癌症疫苗

基本信息

批准号：
7742485
负责人：
Ann B Hill
金额：
$ 20.17万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7742485
关键词：
Adjuvant Antigens Atrophic Attenuated CD34 gene CD8B1 gene Cancer Vaccines Cells Characteristics Chronic Cytomegalovirus Cytomegalovirus Infections Cytomegalovirus Vaccines Dendritic Cells Dose Economic Inflation Engineering Epitopes Event Female Fibroblasts Gene Expression Glycoproteins Goals Human Immune Immune response Immune system Immunity Immunization Immunobiology Immunologic Memory Immunologic Surveillance Immunotherapeutic agent Immunotherapy In Vitro Individual Infection Infertility Life Ligands Macaca mulatta Measures Memory Modeling Monitor Monkeys Mus Neoplasm Metastasis Normal tissue morphology Ovarian Patients Personal Communication Phenotype Proteins Recombinants Recurrence Resistance Route Self Tolerance Stem cells T memory cell T-Lymphocyte Testing Time Tissues Treatment Protocols Tumor Antigens Vaccination Vaccines Viral Virus Zona Pellucida base efficacy testing immunogenic immunogenicity latent infection melanoma monolayer peripheral blood plasmid DNA promoter public health relevance recombinant virus response tumor vaccine efficacy vector vector vaccine vector-based vaccine

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to develop an attenuated cytomegalovirus-based vaccine vector expressing the melanoma antigen trp-1 for use in tumor immunotherapy. Certain features of the immunobiology of CMV suggest that a vaccine based on it could make a unique contribution to the tumor immunotherapy arsenal. It is extraordinarily immunogenic for CD8 T cells; it has been shown to overcome self-tolerance to a tissue specific antigen, and as a vaccine vector it can be used sequentially. However, a live virus has obvious limitations as a vector for immune-compromised tumor patients. We have recently shown that a CMV vector that is completely replication deficient nevertheless establishes latency and can prime the characteristic ongoing massive immune response. The goal of the current project is to develop the replication deficient MCMV strain as a vaccine vector, using the well characterized B16 mouse melanoma model. The majority of the project is devoted to optimizing the immune response that can be elicited by the replication deficient vector. We will compare immunogenicity when the tumor antigen is expressed behind different viral promoters, and determine whether antigen expression and immunogenicity can be enhanced further by the use of adjuvants that drive viral IE gene expression. We will use two measures of vaccine efficacy (a) size of the CD8 T cell response an (b) ability to protect against tumor challenge using B16 cells. PUBLIC HEALTH RELEVANCE: Cytomegalovirus (CMV) infection, which is usually asymptomatic and has been safely used as a vaccine, generates a potent cellular immune response and immunological memory that is maintained for life. Previously, CMV has been engineered to induce the immune system to target normal tissues. Our goal is to harness this potent immune response elicited by CMV to test use as an effective tumor vaccine. A safe vaccine vector that is unable to replicate will be generated for this purpose.

描述（由申请人提供）：该项目的目的是开发一种基于巨细胞病毒的疫苗载体，表达用于肿瘤免疫疗法的黑色素瘤抗原TRP-1。 CMV免疫生物学的某些特征表明，基于其的疫苗可能对肿瘤免疫疗法做出独特的贡献。对于CD8 T细胞，它具有特殊的免疫原性。已证明它可以克服对组织特异性抗原的自耐耐受性，并且作为疫苗载体可以依次使用。然而，作为免疫受损肿瘤患者的载体，活病毒具有明显的局限性。我们最近表明，完全复制缺陷的CMV矢量仍然建立潜伏期，并可以使特征性持续的大规模免疫反应产生延迟。当前项目的目的是使用表征良好的B16小鼠黑色素瘤模型来开发复制缺陷的MCMV菌株作为疫苗载体。该项目的大多数致力于优化可复制不足向量可以引起的免疫反应。当肿瘤抗原在不同的病毒启动子后面表达时，我们将比较免疫原性，并确定抗原表达和免疫原性是否可以通过使用驱动病毒IE基因表达的辅助剂进一步增强。我们将使用两种测量疫苗功效（a）CD8 T细胞响应的大小A（b）使用B16细胞来防止肿瘤攻击的能力。公共卫生相关性：巨细胞病毒（CMV）感染通常是无症状的，并已安全地用作疫苗，会产生有效的细胞免疫反应和免疫记忆，并终身维持的免疫记忆。以前，CMV已设计为诱导免疫系统靶向正常组织。我们的目标是利用CMV引起的这种有效的免疫反应来测试用作有效的肿瘤疫苗。为此目的将生成无法复制的安全疫苗向量。