Rational Design of Therapeutic Vaccines for CEA+ Tumors

CEA肿瘤治疗疫苗的合理设计

• 批准号: 6717510
• 负责人: MALAYA B CHATTERJEE
• 金额: $ 34.15万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6717510
• 关键词: antiidiotype antibody; carcinoembryonal antigen; colon neoplasms; immune tolerance /unresponsiveness; laboratory mouse; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; nonhuman therapy evaluation; vaccine development

DESCRIPTION (provided by applicant): Extensive preclinical studies, as well as results obtained from clinical trials, suggest that vaccination with an anti-idiotype (Id) antibody (3H1) that mimics an epitope of human carcinoembryonic antigen (CEA) has the potential to augment survival benefits. Anti-ld 3H1 breaks immune tolerance to CEA and induces anti-CEA antibody as well as CD4+T helper (Th1) responses in colorectal cancer patients and also in mice transgenic for CEA. This anti-ld approach in its current form, although promising, will need improvements to realize its full potential. Suitable murine tumor models will be used to explore strategies that will significantly improve the therapeutic impact of this vaccine. The proposal is based on the hypothesis that stimulating a CEA-specific CD4+ T cell response, ie T-help, in the host, will provide critical help for priming and activation of CEA-specific CTL, the major effector cells (CD8+ T cells) for tumor destruction. We hypothesize that the combination of CD4+ with CD8+ T cell epitopes will further augment the anti-tumor immune responses. The specific aims of this proposal are: 1) to determine whether vaccination with 3H1, which will generate anti-CEA Ab and T-help, in combination with mRNA derived from CEA, using dendritic cells (DC) as APC, will induce CTL and engender therapeutic immunity in an established tumor model in C57BL/6 mice (H2kb), double transgenic for human CEA and HLA-A2; 2) to explore whether a combination of 3H1 with HLA-A2 restricted known agonist CTL epitopes of CEA, using DC as APC, will work better in the above tumor model; 3) to test whether the idio-peptides, (LCD-2 and CEA-B) derived from the structure of 3H1 and CEA based on the amino acid sequence homology, which also induce CD4+Th1 help will be more immunogenic in combination with the agonist CTL peptides of CEA. The criteria for selection of the optimal regimen for vaccination will be based on the ability to invoke anti-tumor activities in vitro and in vivo. We will measure the antibody titer, in vitro CTL activity, intra-cellular cytokine levels and in vivo tumor regression. In Aim 4, we will further explore methods to boost tumor-specific CD4+ as well as CD8+ T cell responses in vivo by coadministration of agents such as IL-2, IL-12, CpG ODN or anti-CTLA4 antibody. We will test for any possible autoimmune responses in CEA-expressing normal organs of mice by histopathological analysis (Aim 5). Promising strategies indicated by these studies will be finally evaluated in Aim 6 in the murine Apc knock-out transgenic mice expressing CEA and HLA-A2, which arguably, are the best murine model for colon cancer, as it closely resembles the human disease. The results obtained from these studies will help design improved therapeutic vaccines for the treatment of CEA+ tumors and can be incorporated readily into our ongoing clinical programs.

描述（由申请人提供）：广泛的临床前研究以及从临床试验中获得的结果表明，使用抗异构型（ID）抗体（3H1）的疫苗接种模仿人类癌症的表位（CEA）具有增强生存益处的潜力。抗LD 3H1破坏了对CEA的免疫耐受性，并诱导结直肠癌患者以及CEA小鼠TRANSEC中的CD4+T助手（TH1）反应（TH1）反应。这种反现在的方法以其当前形式（尽管很有希望）需要改进才能实现其全部潜力。合适的鼠肿瘤模型将用于探索将显着改善该疫苗治疗影响的策略。该提议基于以下假设：刺激CEA特异性CD4+ T细胞反应，即宿主中的T-螺旋，将为CEA特异性CTL（主要效应细胞（CD8+ T细胞））启动和激活提供关键的帮助。我们假设CD4+与CD8+ T细胞表位的组合将进一步增强抗肿瘤免疫反应。该提案的具体目的是：1）确定使用树突细胞（DC）作为APC，使用3H1的疫苗与3H1的疫苗接种将产生抗CEA AB和T-螺旋，并结合源自CEA的mRNA，将在C57BL/6 M2k的C57BL/6 m2k中诱导CTL和促进肿瘤模型中的CTL和引起肿瘤模型。 HLA-A2; 2）探索3H1与HLA-A2的组合使用DC作为APC限制了CEA的已知激动剂CTL表位，在上述肿瘤模型中会更好地工作； 3）测试基于氨基酸序列同源性源自3H1和CEA结构的IDIO肽（LCD-2和CEA-B）是否会诱导CD4+TH1帮助，将与CEA的激动剂CTL肽结合使用CD4+TH1帮助。选择最佳方案的疫苗接种标准将基于在体外和体内调用抗肿瘤活性的能力。我们将测量抗体滴度，体外CTL活性，细胞内细胞因子水平和体内肿瘤回归。在AIM 4中，我们将进一步探索通过在体内通过诸如IL-2，IL-12，CPG ODN或抗CTLA4抗体的剂共同给药来促进肿瘤特异性CD4+以及体内CD8+ T细胞反应的方法。我们将通过组织病理学分析（AIM 5）测试在表达CEA的正常器官中的任何可能的自身免疫反应（AIM 5）。这些研究表明的有希望的策略最终将在AIM 6中评估，在表达CEA和HLA-A2的鼠APC敲除转基因小鼠中，可以说是结肠癌的最佳鼠模型，因为它与人类疾病非常相似。从这些研究中获得的结果将有助于设计改进的CEA+肿瘤治疗治疗疫苗，并可以轻松地将其纳入我们正在进行的临床计划中。