Development of a Novel CEA Expressing Adenovirus for Treatment

描述（由申请人提供）：该项目的目标是继续开发一种针对CEA的腺病毒载体疫苗，该疫苗可以有效地刺激先前对腺病毒免疫的动物的细胞介导免疫。Ad-CEA疫苗的终点是治疗携带CEA的癌症患者。CEA是一种蛋白质，据报道可作为疫苗治疗靶点。有证据表明，需要广泛的细胞介导免疫（CMI）反应来治疗某些CEA癌。腺病毒（Ad）载体疫苗可诱导CMI反应，并已成为治疗性疫苗递送平台的主要候选疫苗。第一代Ad疫苗已被证明不如预期有效，不良反应值得怀疑。此外，大多数人的预先存在的Ad免疫导致有效性降低。为了解决这些问题，我们开发了一种先进的基于Ad的载体，它缺乏早期基因E1， E3和E2b。这些“e2b缺失”的载体，在聚合酶和前端蛋白基因中缺失，与第一代相比，具有扩展的克隆能力和大大降低病毒晚期基因的表达。多种Ad病毒基因表达的减少已被证明对疫苗开发有利，原因包括抗原竞争减少、表达时间延长、免疫刺激增加和不良反应减少。这些优势在存在预先存在的Ad免疫的情况下是重要的，并为E2b Ad矢量提供了类似隐身的属性。该公司拥有新的Ad载体系统和支持载体生产的E.C7细胞系的独家许可。本研究旨在构建和测试基于新的e2b缺失Ad载体平台的CEA疫苗的有效性，该平台将携带CEA基因。Ad疫苗将测试其诱导CEA记忆CMI反应的潜力，以及它们在Ad-na - ve和Ad-免疫小鼠中的再免疫（增强）潜力。将对小鼠进行监测，看疫苗是否有任何不良影响。该项目将产生一种有效、安全、易生产、稳定、易使用的CEA治疗性疫苗。我们的目标是在一年内利用广告载体平台启动一期临床试验。公共卫生相关性：在这项研究中，我们将进一步开发一种用于Ad- CEA治疗疫苗的先进载体递送系统。需要该系统来突破先前有腺病毒感染（包括大多数人类）的疫苗接种者所呈现的屏障。

DESCRIPTION (provided by applicant): The objective of this project is to continue developing an adenoviral vector vaccine against CEA that is effective in stimulating cell-mediated immunity in animals previously immune to adenovirus. The Ad-CEA vaccine endpoint is to treat patients with CEA bearing cancers. CEA is a protein that has been reported to be useful as a vaccine treatment target. Evidence indicates that a broad cell-mediated immune (CMI) response is needed to treat certain CEA bearing cancers. Adenovirus (Ad) vector vaccines induce CMI responses and have emerged as a leading candidate to be used as a treatment vaccine delivery platform. First Generation Ad vaccines have proven less effective than anticipated and adverse reactions are in question. Furthermore, pre-existing Ad immunity of most humans causes decreased effectiveness. To address these issues, we have developed an advanced Ad based vector that is devoid of early genes E1, E3, and E2b. These "E2b-deleted" vectors, with deletions in the polymerase and preterminal protein genes, have an expanded cloning capacity and greatly reduced expression of viral late genes as compared to First Generation. The reduced expression of multiple Ad viral genes has been demonstrated to be advantageous for vaccine development for reasons such as reduced antigenic competition, greater longevity of expression, which provides increased immunologic stimulus and reduced adverse effects. Such advantages are important in the presence of pre-existing Ad immunity, and provide the E2b Ad vectors stealth-like attributes. The Company has exclusive license for the new Ad vector system and the E.C7 cell line that supports vector production. The proposed studies are designed to construct and test the effectiveness of CEA vaccines based on the new E2b-deleted Ad vector platform, which will carry the CEA gene. Ad vaccines will be tested for their potential to induce CEA memory CMI responses as a prime and for their re-immunization (boost) potential in Ad-na¿ve and Ad- immune mice. The mice will be monitored for any adverse effects of the vaccine. This project will result in an effective, safe, easy to produce, stable, and easy to use CEA therapeutic vaccine. Our goal is to initiate a Phase I clinical trial using an Ad vector platform within a year of funding. PUBLIC HEALTH RELEVANCE: During this study, we will further develop an advanced vector delivery system for an Ad- CEA treatment vaccine. The system is needed to break through the barrier presented by vaccinees that have had prior adenovirus infections which includes most humans.