Adoptive Immunotherapy with Recombinant Adenvirus Vector

重组腺病毒载体的过继免疫治疗

• 批准号: 6989595
• 负责人: Andrea na Amalfitano
• 金额: $ 18.51万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-14 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989595
• 关键词: Adenoviridae; Poxviridae; T lymphocyte; active immunization; biotechnology; carcinoembryonal antigen; clinical research; clinical trial phase I; dendritic cells; human subject; immune response; neoplasm /cancer immunotherapy; patient oriented research; transfection /expression vector; vaccine development; vaccine evaluation; vector vaccine

Several different vaccine strategies have been evaluated and combined in an attempt to amplify T-cell responses toward induction of anti-tumor immunity. The model tumor antigen used in many of these studies was carcinoembryonic antigen (CEA). While initial T-cell activation studies were conducted in conventional mice and then tested, results from the clinical trials suggested immune and clinical responses less dramatic than in the murine models. One strategy to improve the clinical outcome has been the use of recombinant viral vectors encoding CEA modified dendritic cells. Based upon several lines of observation, this strategy appears to be capable of further improvement when using a heterologous prime-boost vaccination strategy, using alternative means of introducing the tumor antigen. Therefore, we propose pre-clinical and clinical studies of combined vaccine strategy studies, in this instance capitalizing upon the known efficacy of fowlpox CEA virus based constructs, but now combining this expertise with use of adenovirus based vectors also encoding CEA. Exciting data from the HIV vaccine literature suggest that heterologous prime-boost vaccine strategies have significantly benefited from the utilization of first generation Ad based vectors, showing dramatically improved evidence of inducing immune critical T-cell responses in human subjects. Uniquely, our group has previously constructed several new generations of Ad vector that will allow us to investigate and optimize the use of Ad vectors as vaccines for a variety of antigens. Once the most optimized Ad encoding CEA is delineated, we will determine the efficacy of the vector alone, or in heterologous prime-boost vaccine strategies utilizing rigorous animal models. A key innovation will be our ability to synergize with the other projects and cores in this program project, for example we will evaluate the anti-tumor efficacy of heterologous prime-boost strategies utilizing the optimal Ad-CEA vector vaccine, combined with either the aforementioned fowlpox-CEA vector vaccine, or an alphavirus based CEA vector vaccine (the latter being developed in Project #2 of this overall proposal). These studies are intended to demonstrate that the use of heterologous prime-boost regimens (via the use of two different recombinant vectors) can further amplify T-cell responses toward tumor associated antigens such as CEA. Finally, we will initiate pre-clinical studies and a pilot project of active immunotherapy using the most optimized adenovirus+CEA vector based vaccine, a prelude to a combined pox/Ad or alphavirus/Ad heterologous prime-boost clinical trial.

已经评估并组合了几种不同的疫苗策略，试图放大 T 细胞对诱导抗肿瘤免疫的反应。许多这些研究中使用的模型肿瘤抗原是癌胚抗原（CEA）。虽然最初的 T 细胞激活研究是在传统小鼠中进行并随后进行测试，但临床试验的结果表明，免疫和临床反应不如小鼠模型那么显着。改善临床结果的一种策略是使用编码 CEA 修饰的树突状细胞的重组病毒载体。基于几条观察线，当使用异源初免-加强疫苗接种策略、使用引入肿瘤抗原的替代方法时，该策略似乎能够进一步改进。因此，我们建议临床前和临床 联合疫苗策略研究，在本例中利用基于鸡痘 CEA 病毒的构建体的已知功效，但现在将这种专业知识与也编码 CEA 的基于腺病毒的载体的使用相结合。 HIV 疫苗文献中令人兴奋的数据表明，异源初免-加强疫苗策略已显着受益于第一代基于 Ad 的载体的利用，显示出在人类受试者中诱导免疫关键 T 细胞反应的显着改善的证据。独特的是，我们的团队之前构建了几代新一代的 Ad 载体，这将使我们能够研究和优化 Ad 载体作为多种​​抗原疫苗的用途。曾经最优化的广告 当编码 CEA 被描述后，我们将确定单独载体的功效，或利用严格的动物模型在异源初免-加强疫苗策略中的功效。一个关键的创新将是我们与该计划项目中的其他项目和核心协同的能力，例如，我们将利用最佳的 Ad-CEA 载体疫苗结合上述任一方法来评估异源初免加强策略的抗肿瘤功效鸡痘-CEA 载体疫苗，或基于甲病毒的 CEA 载体疫苗（后者正在本总体提案的项目 #2 中开发）。这些研究旨在证明使用 异源初免-加强方案（通过使用两种不同的重组载体）可以进一步放大 T 细胞对肿瘤相关抗原（如 CEA）的反应。最后，我们将启动临床前研究和使用最优化的腺病毒+CEA载体疫苗的主动免疫治疗试点项目，这是痘/Ad或甲病毒/Ad异源初免-加强联合临床试验的前奏。