NOVEL STRATEGIES FOR THE IMMUNOTHERAPY OF COLON CANCER

结肠癌免疫治疗的新策略

• 批准号: 6377619
• 负责人: RALPH A. REISFELD
• 金额: $ 39.89万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-08 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6377619
• 关键词: Listeria; Salmonella typhimurium; antigen presentation; carcinoembryonal antigen; chimeric proteins; colon neoplasms; cytotoxic T lymphocyte; disease /disorder model; genetically modified animals; laboratory mouse; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; nonhuman therapy evaluation; passive immunization; proteasome; ubiquitin; vaccine development; vector vaccine; Listeria; Salmonella typhimurium; antigen presentation; carcinoembryonal antigen; chimeric proteins; colon neoplasms; cytotoxic T lymphocyte; disease /disorder model; genetically modified animals; laboratory mouse; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; nonhuman therapy evaluation; passive immunization; proteasome; ubiquitin; vaccine development; vector vaccine

DESCRIPTION: (Adapted from applicant's abstract) The overall objective is to construct and optimize novel human CEA-based DNA vaccines for the effective immunotherapy of colon carcinoma. The investigators will test the hypothesis that peripheral T cell tolerance to these tumor self-antigens can be overcome by DNA vaccines boosted by effective adjuvants designed to generate cytolytic T lymphocyte (CTLs) specific for CEA epitopes expressed as MHC class I complexes on colon carcinoma cells. Emphasis will be on optimizing antigen processing and presentation in mouse models either transgenic for CEA or double transgenic for CEA and HLA-A2.1Kb. Their aim is to use such models for optimization of vaccine by antibody-cytokine fusion proteins and to investigate basic concepts such as mechanisms of T cell co-stimulation, generation of tumor-specific CTLs and T memory cells and establish principles for adoptive immunotherapy. The specific aims designed to achieve these objectives are: 1) construction of optimal human CEA-specific DNA vaccines containing first the entire CEA gene and then minigenes encoding specific CEA peptides with HLA-A*0201 anchor residues. Delivery of the vaccines by injction of naked KNA or orally by galvage using attenuated strains of either Salmonella typhimurium or Listeria monocytogenes; 2) optimization of antigen processing in the 20S proteasome and presentation by using ubiquitinated versions of the entire CEA gene, minigenes encoding several CEA nonapeptides organized as as a string of beads or direct targeting of single CEA or repeat epitopes to the endoplasmic reticulum; 3) achievement of optimal adjuvanticity using either unmethylated CpG dinucleotide motifs or CD40 Ligand/Trimer co-expression; and 4) determination whether antibody-IL2 fusion proteins can effectively boost DNA vaccines to achieve optimal, long-lived tumor-protective immunity, as well as eradicate established metastases, and identification of immunological mechanisms involved in generating tumor-specific CTLs and T memory cells. The achievement of this proposal's objectives should lead to the design of effective DNA vaccines based on rational immunological principles that may ultimately lead to the improved treatment of colon cancer.

描述：（改编自申请人的摘要）总体目标是 构建并优化新型人类CEA基于CEA的DNA疫苗，以实现有效 结肠癌的免疫疗法。研究人员将检验假设 可以克服对这些肿瘤自我抗原的外围T细胞耐受性 由DNA疫苗由旨在产生细胞溶解T的有效佐剂增强 淋巴细胞（CTLS）特异性的CEA表位表示为MHC I类配合物 在结肠癌细胞上。重点将是优化抗原加工和 在小鼠模型中呈现CEA的转基因或双转基因的转基因 CEA和HLA-A2.1KB。他们的目的是使用此类模型来优化疫苗 通过抗体 - 促动物融合蛋白，并研究基本概念，例如 T细胞共刺激的机制，肿瘤特异性CTL和T的产生 记忆细胞并确定采用免疫疗法的原理。具体 旨在实现这些目标的目的是：1）建造最佳人类 CEA特异性DNA疫苗首先包含整个CEA基因，然后 用HLA-A*0201锚固残基编码特定CEA肽的微型烯。 通过使用裸体KNA或口服疫苗的疫苗输送疫苗 鼠伤寒沙门氏菌或单核细胞增生李斯特菌的菌株； 2）在20S蛋白酶体中优化抗原加工，并通过 使用整个CEA基因的泛素化版本，编码几个 CEA非肽被组织为一串珠或直接靶向 单个CEA或重复表现到内质网； 3）成就 使用未甲基化的CPG二核苷酸基序或CD40的最佳辅助性 配体/三聚体共表达； 4）确定抗体-IL2融合是否是否 蛋白质可以有效地增强DNA疫苗以实现最佳，长寿 肿瘤保护的免疫力以及根除已建立的转移和 鉴定引起的免疫机制 肿瘤特异性CTL和T记忆细胞。该提议的成就 目标应导致基于有效DNA疫苗的设计 理性免疫原理可能最终导致改善 结肠癌的治疗。