A vaccine to break tolerance to cervical carcinoma oncoprotein

有证据表明宫颈癌是由人乳头瘤病毒引起的，这一证据令人信服。一旦病毒进入宫颈细胞，它就会产生一种名为E7的蛋白质，这种蛋白质的功能是使细胞癌变。宫颈癌是澳大利亚女性的第五大常见死因，也是全球女性的主要杀手。E7蛋白是疫苗的理想靶点，因为它只出现在肿瘤细胞中。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。我们的实验室已经开发了几种人类宫颈癌的小鼠模型，并已经找出了E7蛋白的哪些部分在发展适当的免疫反应以控制肿瘤生长方面是重要的。然而，一个主要的发现是，E7分子使CTL细胞群体无法做出适当的反应来杀死肿瘤细胞。我们相信，这个过程，称为‘耐受性诱导’，可以通过使用如下的新方法来克服。被称为树突状细胞(DC)的特殊抗原提呈细胞将被分离出来，并通过感染基因修饰的病毒(腺病毒)来产生E7蛋白，这种病毒表达E7和特殊的DC激活剂分子，但不能自我复制。树突状细胞将作为疫苗重新引入宿主，并将E7以一种打破耐受性的方式呈现给免疫系统。换句话说，疫苗接受者将再次能够对肿瘤中的E7蛋白产生CTL免疫反应，从而能够杀死肿瘤细胞。

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.