Antitumor efficacy of Venezuelan equine encephalitis virus replicon particles encoding mutated HPV16 E6 and E7 genes
Antitumor efficacy of Venezuelan equine encephalitis virus replicon particles encoding mutated HPV16 E6 and E7 genes
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DOI：
10.1016/j.vaccine.2003.07.003
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发表时间：
2004-01-02
期刊：
影响因子：
5.5
通讯作者：
Kast, WM
中科院分区：
文献类型：
--
作者：
Cassetti, MC;McElhiney, SP;Kast, WM
用于治疗人乳头瘤病毒（HPV）相关的恶性肿瘤（如宫颈癌）的有效疫苗应引发针对恶性状态所必需的E6和/或E7蛋白的强T细胞介导的免疫（CMI）。我们已经开发了编码HPV 16 E6和E7基因的委内瑞拉马脑炎（VEE）病毒复制子颗粒（VRP）疫苗，并测试了它们的免疫原性和抗肿瘤效力。将E6和E7基因融合以创建一个开放阅读框，并在四个或五个氨基酸位置处突变以失活其致癌潜力。编码突变型或野生型E6和E7蛋白的VRP引起对免疫显性E7（49-57）表位的相当的细胞毒性T淋巴细胞（CTL）应答，并在几种HPV 16 E6（+）E7（+）肿瘤攻击模型中产生相当的抗肿瘤应答：在100%的VRP接种小鼠中观察到对C3或TC-1肿瘤攻击的保护。在治疗性VRP疫苗接种后，在约90%的小鼠中观察到C3肿瘤的根除。在治疗性VRP疫苗接种后，在90%的人类白细胞抗原（HLA）-A（*）0201转基因小鼠中观察到缺乏E749-57表位的HLF 16肿瘤根除。最后，预测的失活E6和E7致癌潜力证实了证明正常水平的p53和视网膜母细胞瘤蛋白在人乳腺上皮细胞（MEC）感染VRP表达突变E6和E7基因。这些有希望的结果支持继续开发突变E6和E7 VRP作为针对HPV相关疾病的临床评价的安全有效的候选物。(C)2003 Elsevier Ltd.保留所有权利。
An effective vaccine for treating human papillomavirus (HPV)-associated malignancies such as cervical cancer should elicit strong T cell-mediated immunity (CMI) against the E6 and/or E7 proteins necessary for the malignant state. We have developed Venezuelan equine encephalitis (VEE) virus replicon particle (VRP) vaccines encoding the HPV 16 E6 and E7 genes and tested their immunogenicity and antitumor efficacy. The E6 and E7 genes were fused to create one open reading frame and mutated at four or at five amino acid positions to inactivate their oncogenic potential. VRP encoding mutant or wild type E6 and E7 proteins elicited comparable cytotoxic T lymphocyte (CTL) responses to an immunodominant E7(49-57) epitope and generated comparable antitumor responses in several HPV16 E6(+)E7(+) tumor challenge models: protection from either C3 or TC-1 tumor challenge was observed in 100% of VRP-vaccinated mice. Eradication of C3 tumors was observed in approximately 90% of mice following therapeutic VRP vaccination. Eradication of HLF16 tumors lacking the E749-57 epitope was observed in 90% of human leukocyte antigen (HLA)-A(*)0201 transgenic mice following therapeutic VRP vaccination. Finally, the predicted inactivation of E6 and E7 oncogenic potential was confirmed by demonstrating normal levels of both p53 and retinoblastoma proteins in human mammary epithelial cells (MEC) infected with VRP expressing mutant E6 and E7 genes. These promising results support the continued development of mutant E6 and E7 VRP as safe and effective candidates for clinical evaluation against HPV-associated disease. (C) 2003 Elsevier Ltd. All rights reserved.