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.

已经评估和合并了几种不同的疫苗策略，以扩大对诱导抗肿瘤免疫力的T细胞反应。这些研究中使用的模型肿瘤抗原是癌胚抗原（CEA）。虽然在常规小鼠中进行了最初的T细胞激活研究，然后进行了测试，但临床试验的结果表明，与鼠模型相比，免疫和临床反应更为明显。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，使用引入肿瘤抗原的替代方法时，使用异源促进疫苗接种策略时，该策略似乎能够进一步改善。因此，我们提出了临床前和临床 对疫苗策略研究的研究，在这种情况下，利用了基于Fowlpox CEA病毒构建体的已知功效，但是现在将这种专业知识与使用基于腺病毒的矢量的媒介相结合，也编码CEA。来自HIV疫苗文献的令人兴奋的数据表明，异源促进疫苗策略已大大受益于第一代基于AD的载体，显示出巨大的改进的证据证明了人类受试者中诱导免疫临界T细胞反应的证据。独特的是，我们的小组以前已经构建了几个新一代的AD媒介，这将使我们能够调查并优化AD载体作为各种抗原的疫苗的使用。曾经是最优化的广告 描述了编码CEA，我们将仅使用严格的动物模型来确定矢量的功效，或者在异源促进疫苗策略中的效力。 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 提议）。这些研究旨在证明使用 异源质子促进方案（通过使用两种不同的重组载体）可以进一步扩大对肿瘤相关抗原（如CEA）的T细胞反应。最后，我们将使用最优化的腺病毒+CEA载体疫苗进行临床前研究和主动免疫疗法的试验项目，这是鼠疫/AD或AD AD AD异源原质促进临床试验的前奏。