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首页> 外文期刊>Human gene therapy. Clinical development >Efficacy of DNA Vaccines Forming E7 Recombinant Retroviral Virus-Like Particles for the Treatment of Human Papillomavirus-lnduced Cancers
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Efficacy of DNA Vaccines Forming E7 Recombinant Retroviral Virus-Like Particles for the Treatment of Human Papillomavirus-lnduced Cancers

机译：形成E7重组逆转录病毒样颗粒的DNA疫苗治疗人乳头瘤病毒引起的癌症的功效

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Human papillomavirus (HPV) is involved in the development of anogenital tumors and also in the development of oropharyngeal head and neck carcinomas, where HPV-16, expressing the E6 and E7 oncoproteins, is the most frequent serotype. Although vaccines encoding LI and L2 capsid HPV proteins are efficient for the prevention of HPV infection, they are inadequate for treating established tumors. Hence, development of innovative vaccine therapies targeting E6/E7 is important for controlling HPV-induced cancers. We have engineered a nononcogenic mutated E7-specific plasmo-retroVLP vaccine (pVLP-E7), consisting of plasmid DNA, that is able to form recombinant retrovirus-based virus-like particles (VLPs) that display E7 antigen into murine leukemia virus Gag proteins pseudotyped with vesicular stomatitis virus envelope glycoprotein (VSV-G). pVLP-E7 vaccinations were studied for their ability to generate specific immune responses and for induction of protective immunity against tumor cell challenge in preventive and therapeutic models. The produced VLPs induce the maturation of human dendritic cells in vitro and mount specific E7 T cell responses. Intradermic vaccinations of mice with pVLP-E7 show their efficacy to generate antigen-specific T cell responses, to prevent and protect animals from early TC-1 tumor development compared with standard DNA or VLP immunizations. The vaccine efficacy was also evaluated for advanced tumors in mice vaccinated at various time after the injection of TC-1 cells. Data show that pVLP-E7 vaccination can cure mice with already established tumors only when combined with Toll-like receptor-7 (TLR7) and TLR9 agonists. Our findings provide evidence that pVLPs, combining the advantages of DNA and VLP vaccines, appear to be a promising strategy for the treatment of HPV-induced cancers.
机译：人乳头瘤病毒（HPV）参与肛门生殖器肿瘤的发展以及口咽头颈癌的发展，其中表达E6和E7癌蛋白的HPV-16是最常见的血清型。尽管编码L1和L2衣壳HPV蛋白的疫苗可有效预防HPV感染，但不足以治疗已建立的肿瘤。因此，开发针对E6 / E7的创新疫苗疗法对于控制HPV诱导的癌症非常重要。我们设计了一种非致癌的突变E7特异性plasmo-retroVLP疫苗（pVLP-E7），由质粒DNA组成，能够形成基于重组逆转录病毒的病毒样颗粒（VLP），将E7抗原展示到鼠白血病病毒Gag蛋白中水泡性口炎病毒包膜糖蛋白（VSV-G）的假型。在预防和治疗模型中，研究了pVLP-E7疫苗产生特定免疫反应的能力以及诱导针对肿瘤细胞攻击的保护性免疫的能力。产生的VLP在体外诱导人树突状细胞成熟，并引起特异性E7 T细胞应答。与标准DNA或VLP免疫相比，pVLP-E7小鼠的真皮内疫苗接种显示出产生抗原特异性T细胞反应，预防和保护动物免受早期TC-1肿瘤发展的功效。还评估了在注射TC-1细胞后不同时间接种的小鼠中晚期肿瘤的疫苗效力。数据显示，仅当与Toll样受体7（TLR7）和TLR9激动剂联合使用时，pVLP-E7疫苗接种才能治愈已建立肿瘤的小鼠。我们的发现提供了证据，证明结合了DNA和VLP疫苗优势的pVLP似乎是治疗HPV诱导的癌症的有前途的策略。

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