MECHANISMS OF ADENOVIRUS VACCINES FOR COLON CANCER

该项目的主要目标是确定一种最佳的腺病毒- 基于人类同源基因(MEGP)的疫苗接种策略 结直肠癌相关的GA733抗原。由于小鼠表达mEGP 正常组织(类似于人类的GA733抗原)，该动物模型允许 疫苗在免疫耐受宿主中的测试和评价 潜在的毒性。这些研究将优化这一能力 在以下情况下克服这种肿瘤抗原耐受性的疫苗 与结肠癌患者非常相似。因此，他们将有一个 对最初的人体临床试验的影响(见项目3，目标2)，并将 为改进的人结肠癌疫苗的测试提供依据 在不久的将来。我们已经制备了一种基于腺病毒的mEGP疫苗，并 已经证明它可以在小鼠体内诱导肿瘤保护，当 与白介素2(IL-2)联合使用。这是我们的基础 提出了一系列实验。我们最初的实验将解决 与临床直接相关的问题，即 通过皮肤途径接种疫苗，需要一剂而不是两剂 疫苗，以及细胞因子的适当使用。具有标识的参数 在皮下肿瘤模型中限制或增强我们的疫苗，我们将 然后解决我们的疫苗接种策略是否对更多 晚期和转移性疾病。这将为我们提供机会 通过研究不同助剂的效果来改进我们的疫苗 策略，其他细胞因子的使用和功能活性的使用 MEGP的片段(摘自项目1)。优化了我们的疫苗后，我们将 通过定义靶细胞来研究其作用机制 腺病毒诱导抗mEGP免疫，腺病毒的作用 在诱导免疫反应中的蛋白质，以及能够 有助于提高免疫反应的有效性。

The major goal of this project is to identify an optimal adenovirus- based vaccination strategy against homologue (mEGP) of the human colorectal carcinoma-associated GA733 antigen. Since mice express mEGP on normal tissues (similar to GA733 Ag in humans), this animal model allows testing of the vaccine in an immunologically tolerant host and evaluation of potential toxicity. These studies will optimize the ability of this vaccine to overcome tolerance to this tumor antigen in settings that closely mimic patients with colon cancer. Therefore, they will have an impact on the initial human clinical trial (see Project 3, Aim 2) and will provide the basis for the testing of improved human colon cancer vaccines in the near future. We have prepared an adenovirus-based mEGP vaccine and have already shown that it can induce tumor protection in the mouse when used in combination with interleukin-2 (IL-2). This is the basis for our proposed series of experiments. Our initial experiments will address issues of immediate clinical relevance, i.e., administration of the vaccine by a cutaneous route, the need for one versus two doses of the vaccine, and the appropriate use of cytokine. Having identified parameters that limit or enhance our vaccine in a subcutaneous tumor model, we will than address whether our vaccination strategy is effective against more advanced and metastatic disease. This will provide us with the opportunity to improve our vaccine by studying the effects of different booster strategies, the use of other cytokines and the use of functionally active fragments (from Project 1) of mEGP. Having optimized our vaccine, we will study its mechanism of action by defining the target cells through which the adenovirus elicits anti-mEGP immunity, the role of the adenoviral proteins in the induction of the immune response, and the cell types that contribute to the effectiveness of the immune response.