A polyepitope HPV16 E7 DNA vaccine restricted through multiple class 1 haplotypes protects against E7-expressing tumour

通过多个 1 类单倍型限制的多表位 HPV16 E7 DNA 疫苗可预防表达 E7 的肿瘤

• 批准号: nhmrc : 102458
• 负责人: Prof Robert Tindle
• 金额: $ 14.55万
• 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 2002-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/polyepitope-hpv16-e7-expressing-tumour/82434
• 关键词: polyepitope; HPV16; E7; DNA; vaccine

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 5th commonest cause of death in women in Australia, and the major killer of women world-wide.The disease is particularly severe in those women whose immune systems are impaired, indicating immunological control of the cancerous cells . Current therapies including surgical removal are frequently inadequate, and the r is no effective drug to combat the virus.These observations indicate that a vaccine is warranted, and that the E7 protein may be an ideal target for the vaccine. Cervical tumour cells are killed by specialised immune system cells named CTLs which recognise fragments of foreign antigen(E7) on their surface bound to selfMHC molecules. Our work has shown that multiple antigen fragments can be encoded and stitched together in a genetic vaccine which will stimulate CTLs to function in a number of 'self'molecule situations Our laboratory has developed several mouse models of human cervical cancer , and (along with others) has worked out which parts of the E7 protein are importatnt in developing an appropriate immune response to control tumour growth when given as a vaccine. One animal model consists of mice which are genetically engineered to produce several types of selfmolecules and also E7. Thes mice develop skin tumours as result of E7 expression. This system provides model of cervical epithelial tumours caused by E7 expression in women.Thus we can ask the questions o can we elicit CTL responses which function in the context of humanself ? o Will these CTL responses prevent the growth of E7-induced epithelial tumours? The OUTCOME of the project will be a vaccine which will prevent the establishment of cervical cancer which can progress directly into clinical trials in women bearing appropriate selfmolecules.

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。这种疾病在免疫系​​统受损的女性中尤为严重，这表明癌细胞受到免疫控制。目前的疗法（包括手术切除）常常不足，并且没有有效的药物来对抗病毒。这些观察表明疫苗是必要的，并且 E7 蛋白可能是疫苗的理想靶标。宫颈肿瘤细胞被称为 CTL 的特殊免疫系统细胞杀死，这些细胞识别其表面与自身 MHC 分子结合的外源抗原 (E7) 片段。我们的工作表明，可以在基因疫苗中编码和缝合多个抗原片段，这将刺激 CTL 在许多“自身”分子情况下发挥作用。我们的实验室开发了几种人类宫颈癌的小鼠模型，并且（与其他人一起）已经弄清楚了 E7 蛋白的哪些部分在作为疫苗给予时，对于产生适当的免疫反应以控制肿瘤生长至关重要。一种动物模型由经过基因工程改造的小鼠组成，可产生多种类型的自身分子以及 E7。 E7 表达导致这些小鼠出现皮肤肿瘤。该系统提供了由女性 E7 表达引起的宫颈上皮肿瘤模型。因此我们可以提出这样的问题：我们能否引发在人类自身环境中发挥作用的 CTL 反应？ o 这些 CTL 反应会阻止 E7 诱导的上皮肿瘤的生长吗？该项目的成果将是一种预防宫颈癌的疫苗，该疫苗可以直接进入带有适当自身分子的女性的临床试验。