NOVEL STRATEGIES FOR THE IMMUNOTHERAPY OF COLON CANCER

结肠癌免疫治疗的新策略

• 批准号: 6196918
• 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/6196918
• 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

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：（改编自申请人摘要）总体目标是 构建并优化新型人CEA DNA疫苗， 结肠癌免疫治疗调查人员将检验这一假设 可以克服外周T细胞对这些肿瘤自身抗原的耐受性 通过DNA疫苗加强有效的佐剂设计，以产生细胞溶解T 表达为MHC I类复合物的CEA表位特异性淋巴细胞（CTL） 结肠癌细胞上。重点将放在优化抗原处理和 在CEA转基因或CEA双转基因小鼠模型中的表达 CEA和HLA-A2. 1 Kb.他们的目的是使用这种模型来优化疫苗 通过抗体-细胞因子融合蛋白，并研究基本概念， T细胞共刺激机制、肿瘤特异性CTL的产生和T细胞介导的免疫应答 记忆细胞和建立过继免疫治疗的原则。具体 为实现这些目标而设计的目标是：1）构建最佳人力资源 CEA特异性DNA疫苗首先含有整个CEA基因，然后 编码具有HLA-A*0201锚残基的特异性CEA肽的小基因。 通过注射裸露的KNA或口服Galvage进行疫苗接种， 鼠伤寒沙门氏菌或单核细胞增生李斯特菌的减毒菌株; 2)20 S蛋白酶体中抗原加工的优化和 使用整个CEA基因的泛素化版本，编码几个 CEA九肽组织为一串珠子或直接靶向 单个CEA或内质网重复表位; 3）实现 使用未甲基化的CpG二核苷酸基序或CD 40 配体/三聚体共表达;和4）确定抗体-IL 2融合是否 蛋白质可以有效地促进DNA疫苗， 肿瘤保护性免疫，以及根除已建立的转移，和 免疫学机制的鉴定 肿瘤特异性CTL和T记忆细胞。该提案的实现 目标应该导致有效的DNA疫苗的设计， 合理的免疫学原则，最终可能导致改善 结肠癌的治疗