DNA Vaccine Encoding HPV16 Oncogenes E6 and E7 Induces Potent Cell-mediated and Humoral Immunity Which Protects in Tumor Challenge and Drives E7-expressing Skin Graft Rejection.
DNA Vaccine Encoding HPV16 Oncogenes E6 and E7 Induces Potent Cell-mediated and Humoral Immunity Which Protects in Tumor Challenge and Drives E7-expressing Skin Graft Rejection.
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DOI：
10.1097/cji.0000000000000156
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Frazer IH
中科院分区：
文献类型：
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作者：
Chandra J;Dutton JL;Li B;Woo WP;Xu Y;Tolley LK;Yong M;Wells JW;R Leggatt G;Finlayson N;Frazer IH
补充数字内容可在文本中找到。我们以前已经表明，一种新的DNA疫苗技术的密码子优化和添加泛素序列增强免疫原性的单纯疱疹病毒2型多核苷酸疫苗在小鼠中，并诱导细胞介导的免疫力时，在人体内施用相对低剂量的裸DNA。我们在这里表明，一种新的多核苷酸疫苗，使用相同的技术和编码的E6和E7融合蛋白的高危型人乳头瘤病毒16型（HPV 16）的癌基因是免疫原性的小鼠。该疫苗诱导持久的体液和细胞介导的免疫，并保护小鼠免于建立表达HPV 16-E7的肿瘤。此外，它还能抑制容易形成的肿瘤的生长，并在与靶向PD-L1的免疫检查点阻断剂联合使用时显示出增强的疗效。该疫苗还促进了表达HPV 16-E7的皮肤移植物的排斥反应，这些皮肤移植物表现出具有宫颈和外阴上皮内瘤变特征的表皮增生。计划开展临床研究，评估该疫苗在HPV 16+癌前病变患者中的疗效。
Supplemental Digital Content is available in the text. We have previously shown that a novel DNA vaccine technology of codon optimization and the addition of ubiquitin sequences enhanced immunogenicity of a herpes simplex virus 2 polynucleotide vaccine in mice, and induced cell-mediated immunity when administered in humans at relatively low doses of naked DNA. We here show that a new polynucleotide vaccine using the same technology and encoding a fusion protein of the E6 and E7 oncogenes of high-risk human papillomavirus type 16 (HPV16) is immunogenic in mice. This vaccine induces long-lasting humoral and cell-mediated immunity and protects mice from establishment of HPV16-E7-expressing tumors. In addition, it suppresses growth of readily established tumors and shows enhanced efficacy when combined with immune checkpoint blockade targeted at PD-L1. This vaccine also facilitates rejection of HPV16-E7-expressing skin grafts that demonstrate epidermal hyperplasia with characteristics of cervical and vulvar intraepithelial neoplasia. Clinical studies evaluating the efficacy of this vaccine in patients with HPV16+ premalignancies are planned.