Adoptive Immunotherapy with Recombinant Adenvirus Vector

重组腺病毒载体的过继免疫治疗

• 批准号: 7108679
• 负责人: Andrea na Amalfitano
• 金额: $ 19.06万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7108679
• 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.

已经对几种不同的疫苗策略进行了评估和组合，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身上进行的，然后进行了测试，但临床试验的结果表明，免疫和临床反应没有小鼠模型那么显著。改善临床结果的一个策略是使用编码CEA修饰的树突状细胞的重组病毒载体。根据几条观察路线，当使用异种初始-增强疫苗接种策略，使用引入肿瘤抗原的替代方法时，这一策略似乎能够进一步改进。因此，我们建议临床前和临床 联合疫苗策略研究的研究，在这种情况下，利用基于鸡痘CEA病毒的已知有效性，但现在将这一专业知识与也编码CEA的基于腺病毒的载体的使用相结合。来自HIV疫苗文献的令人兴奋的数据表明，异种Prime-Boost疫苗策略已显著受益于第一代基于Ad的载体的使用，显示出在人类受试者中诱导免疫临界T细胞反应的显著改进的证据。独一无二的是，我们的团队之前已经构建了几代新的Ad载体，这将使我们能够研究和优化将Ad载体用作各种抗原的疫苗。曾经最优化的广告 编码CEA后，我们将利用严格的动物模型，单独确定载体的效力，或在异源Prime-Boost疫苗策略中确定其效力。一项关键的创新将是我们与该计划项目中的其他项目和核心的协同能力，例如，我们将使用最优的Ad-CEA载体疫苗，结合上述鸡痘-CEA载体疫苗或基于甲型病毒的CEA载体疫苗(后者在本总体提案的项目#2中开发)来评估异种Prime-Boost策略的抗肿瘤效果。这些研究的目的是证明使用 异种Prime-Boost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载体疫苗进行主动免疫治疗的试点项目，这是联合POX/Ad或AlphaVirus/Ad异源Prime-Boost临床试验的前奏。