A vaccine to break tolerance to cervical carcinoma oncoprotein

一种打破宫颈癌癌蛋白耐受性的疫苗

• 批准号: nhmrc : 143044
• 负责人: Prof Robert Tindle
• 金额: $ 14.14万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2001
• 资助国家: 澳大利亚
• 起止时间: 2001-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/vaccine-break-tolerance-carcinoma-oncoprotein/96336
• 关键词: vaccine; break; tolerance; cervical; carcinoma

Evidence that cervical cancer is caused by Human Papillomavirus is compelling. Once the virus enters the cells of the cervix, it produces a protein named E7 which functions to make the cells cancerous. Cervical cancer is the fifth commonest cause of death in women in Australia, and the major killer of women world-wide. The E7 protein is the ideal target for a vaccine since it occurs only in the tumour cells. Cervical tumour cells are killed by specialised immune system cells termed CTLs which recognised fragments of the E7 molecule on their surface, bound to 'self' MHC molecules. Our laboratory has developed several mouse models of human cervical cancer, and has worked out which parts of the E7 protein are important in developing an appropriate immune response to control tumour growth. However a major finding is that the E7 molecules render the CTL cell population incapable of making an appropriate response to kill the tumour cells. We believe that this process, termed 'tolerance induction' can be overcome by using a novel approach as follows. Specialised antigen presenting cells , termed 'dendritic cells' (DCs) will be isolated and made to produce E7 protein by infecting them with a geneticlly modified virus (Adenovirus) which expresses E7 and specialised DC activators molecules, but is incapable of itself replicating. The dendritic cells will be re-introduced into the host as a vaccine, and will present the E7 to the immune system in such a way that tolerance will be broken. In other words the vaccine recipient will again be able to make a CTL immune response to the E7 protein in their tumours, and so be able to kill the tumour cells.

有证据表明宫颈癌是由人乳头瘤病毒引起的。一旦病毒进入子宫颈细胞，它就会产生一种名为 E7 的蛋白质，其作用是使细胞癌变。宫颈癌是澳大利亚女性第五大常见死因，也是全世界女性的主要杀手。 E7 蛋白是疫苗的理想靶标，因为它只存在于肿瘤细胞中。宫颈肿瘤细胞被称为 CTL 的特殊免疫系统细胞杀死，CTL 识别其表面的 E7 分子片段，并与“自身”MHC 分子结合。我们的实验室开发了几种人类宫颈癌的小鼠模型，并找出了 E7 蛋白的哪些部分对于产生适当的免疫反应以控制肿瘤生长非常重要。然而，一个主要发现是 E7 分子使 CTL 细胞群无法做出适当的反应来杀死肿瘤细胞。我们相信，这个被称为“耐受诱导”的过程可以通过使用如下新颖的方法来克服。被称为“树突状细胞”(DC) 的特殊抗原呈递细胞将被分离出来，并通过用基因改造病毒（腺病毒）感染它们来产生 E7 蛋白，该病毒表达 E7 和专门的 DC 激活剂分子，但自身无法复制。树突状细胞将作为疫苗重新引入宿主，并将E7呈递给免疫系统，从而打破耐受性。换句话说，疫苗接种者将能够再次对其肿瘤中的 E7 蛋白产生 CTL 免疫反应，从而能够杀死肿瘤细胞。