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

• 批准号: 7796744
• 负责人: Ann B Hill
• 金额: $ 16.78万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 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/7796744
• 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; Regimen; Resistance; Route; Self Tolerance; Stem cells; T cell response; T memory cell; T-Lymphocyte; Testing; Time; Tissues; 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

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(申请人提供)：该项目的目标是开发一种表达黑色素瘤抗原Trp-1的基于巨细胞病毒的减毒疫苗载体，用于肿瘤免疫治疗。巨细胞病毒免疫生物学的某些特征表明，基于它的疫苗可以为肿瘤免疫治疗做出独特的贡献。它对CD8T细胞具有极强的免疫原性；它已被证明可以克服对组织特异性抗原的自我耐受性，并且作为疫苗载体可以连续使用。然而，活病毒作为免疫受损的肿瘤患者的载体有明显的局限性。我们最近已经证明，完全复制缺陷的CMV载体仍然会建立潜伏期，并可以启动特征的正在进行的大规模免疫反应。本项目的目标是利用具有良好特性的B16小鼠黑色素瘤模型，开发复制缺陷的MCMV株作为疫苗载体。该项目的大部分致力于优化复制缺陷载体可以引发的免疫反应。我们将比较肿瘤抗原在不同病毒启动子后面表达时的免疫原性，并确定是否可以通过使用驱动病毒IE基因表达的佐剂来进一步增强抗原表达和免疫原性。我们将使用两个衡量疫苗效力的指标(A)CD8 T细胞反应的大小和(B)使用B16细胞预防肿瘤攻击的能力。 公共卫生相关性：巨细胞病毒(CMV)感染通常是无症状的，已被安全地用作疫苗，可产生强大的细胞免疫反应和免疫记忆，并可终身保持。此前，巨细胞病毒被设计成诱导免疫系统以正常组织为目标。我们的目标是利用CMV引起的这种强大的免疫反应来测试作为一种有效的肿瘤疫苗的使用。为此，将产生一种无法复制的安全疫苗载体。