Efficacy - Characterization of Potential Antigens for Immunization Against Colon

功效 - 结肠免疫潜在抗原的表征

• 批准号: 8559620
• 金额: $ 65.07万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 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/8559620
• 关键词: Adenocarcinoma; Age; Animal Model; Animals; Antigens; C57BL/6 Mouse; Cancer Etiology; Carcinoma; Cessation of life; Chemopreventive Agent; Colon; Colon Carcinoma; Cyclooxygenase Inhibitors; Development; Human; Immunization; Intestinal Cancer; Lesion; Literature; Longevity; Malignant Neoplasms; Modeling; Mus; Mutation; Polyvalent Vaccine; Prevention; Proteins; RNA analysis; Rattus; Rodent Model; Sampling; Screening procedure; Small Intestines; Testing; Time; Tumor Antigens; Tumor Burden; Tumor-Associated Process; Vaccine Antigen; Vaccines; Woman; adenoma; base; cancer immunotherapy; cancer prevention; human disease; men; mouse model; novel; prevent; tool; tumor; vaccine development

The successful identification of novel tumor antigens is critical to cancer immunotherapy and its potential use in cancer prevention. Colon cancer is the third most common cancer in both men and women and is the second most common cause of cancer death. Rodent models (Apc Min, AOM induced tumors in mice and rats) that mimic human disease provide a unique tool for tumor antigen discovery. There are varieties of approaches towards deciding upon antigens that might be employed to develop a vaccine. In the case where there is a highly over expressed protein that appears to be directly associated with tumor development (e.g., Neu in Neu over-expressing tumors), this appears to be a promising approach both in animal models and clinically. A second approach is to pick antigens which are over expressed in both mouse and human tumors, and which appear to be associated with the tumor process. It is this latter approach that the studies will employ here. The specific animal model the studies will employ here is a modified ApcMin or Min mouse model. Although the standard Min model, on a C57BL6 background, has proven effective in screening potential chemopreventive agents, it has a major limitation for vaccine studies. The adenomas arise rapidly so that an animal will already have multiple adenomas at the time that immunization is initiated. Furthermore, Min adenomas rarely progress to full carcinomas, which may be due to shortened lifespan as almost all Min mice die by ~100 days of age due to tumor burden. To overcome this, the studies will be conducted with an F1 Min mouse (C57BL/6-APCMin/J x AKR). In this case, tumors arise more slowly, which allows immunization of animals with minimal tumor burden. F1 Min animals survive long enough (up to 300 days) that they develop adenocarcinomas in the small intestine and a significant number of lesions of the colon unlike the standard Min mice.

新型肿瘤抗原的成功鉴定对癌症免疫疗法至关重要及其在预防癌症中的潜在用途。结肠癌是男性和女性中第三大常见的癌症，是癌症死亡的第二大最常见原因。啮齿动物模型（APC最小，AOM诱导的小鼠和大鼠肿瘤）模仿人类疾病为肿瘤抗原发现提供了独特的工具。 有多种方法来决定开发疫苗的抗原。如果存在高度表达的蛋白质，它似乎与肿瘤发育直接相关（例如，在NEU过表达肿瘤中的NEU）中，这似乎是动物模型和临床上的一种有希望的方法。第二种方法是选择在小鼠和人类肿瘤中都过度表达的抗原，并且似乎与肿瘤过程有关。研究将在这里采用后一种方法。 该研究将在这里采用的特定动物模型是修饰的APCMIN或最小小鼠模型。尽管在C57BL6背景上的标准最小模型已被证明有效筛选潜在的化学预防剂，但它在疫苗研究中有一个主要的限制。腺瘤迅速产生，因此动物在开始免疫时已经有多个腺瘤。此外，最小腺瘤很少会发展为全癌，这可能是由于寿命缩短，因为几乎所有的最小小鼠因肿瘤负担而死亡〜100天。为了克服这一点，研究将使用F1分钟小鼠（C57BL/6-apcmin/j X AKR）进行研究。在这种情况下，肿瘤的出现较慢，这允许对具有最小肿瘤负担的动物进行免疫。 F1分钟的动物的生存时间足够长（长达300天），以使其在小肠中发展腺癌，并且与标准的最小小鼠不同。