Adoptive Immunotherapy with Recombinant Adenvirus Vector

已经评估了几种不同的疫苗策略并将其组合以试图放大T细胞应答以诱导抗肿瘤免疫。在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细胞活化研究是在常规小鼠中进行的，然后进行了测试，但临床试验的结果表明，免疫和临床反应不如小鼠模型中那么明显。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，当使用异源初免-加强免疫接种策略时，使用引入肿瘤抗原的替代手段，该策略似乎能够进一步改进。因此，我们建议临床前和临床 联合疫苗策略研究的研究，在这种情况下利用了基于鸡痘CEA病毒的构建体的已知功效，但是现在将这种专门技术与也编码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，异源初免-加强疫苗策略显著受益于第一代基于Ad的载体的利用，显示出在人类受试者中诱导免疫关键性T细胞应答的显著改善的证据。独特的是，我们的小组先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Ad载体作为各种抗原的疫苗的使用。曾经最优化的广告 在描述编码CEA的载体的情况下，我们将利用严格的动物模型确定单独的载体或在异源初免-加强疫苗策略中的效力。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Ad-CEA载体疫苗结合上述鸡痘-CEA载体疫苗或基于甲病毒的CEA载体疫苗（后者在本总体提案的项目#2中开发）来评估异源初免-加强策略的抗肿瘤功效。这些研究旨在证明， 异源初免-加强方案（通过使用两种不同的重组载体）可以进一步扩增针对肿瘤相关抗原如CEA的T细胞应答。最后，我们将启动临床前研究和使用最优化的基于腺病毒+CEA载体的疫苗的主动免疫治疗的试点项目，这是组合的痘病毒/Ad或甲病毒/Ad异源初免-加强临床试验的前奏。

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.