Chandra Janin, Dutton Julie L, Li Bo, Woo Wai-Ping, Xu Yan, Tolley Lynn K, Yong Michelle, Wells James W, R Leggatt Graham, Finlayson Neil, Frazer Ian H
*Admedus Vaccines Pty Ltd †Diamantina Institute, University of Queensland, Brisbane, Qld, Australia.
J Immunother. 2017 Feb/Mar;40(2):62-70. doi: 10.1097/CJI.0000000000000156.
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.
我们之前已经表明，一种新型的密码子优化和添加泛素序列的DNA疫苗技术增强了单纯疱疹病毒2多核苷酸疫苗在小鼠中的免疫原性，并且当以相对低剂量的裸DNA施用于人类时可诱导细胞介导的免疫。我们在此表明，使用相同技术并编码高危人乳头瘤病毒16型（HPV16）E6和E7癌基因融合蛋白的一种新的多核苷酸疫苗在小鼠中具有免疫原性。这种疫苗可诱导持久的体液免疫和细胞介导的免疫，并保护小鼠免受表达HPV16-E7的肿瘤的形成。此外，它可抑制已形成肿瘤的生长，并且当与靶向PD-L1的免疫检查点阻断联合使用时显示出增强的疗效。这种疫苗还促进对表达HPV16-E7的皮肤移植物的排斥，这些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。计划开展评估这种疫苗对HPV16癌前病变患者疗效的临床研究。
