Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
PLoS One. 2013 Jun 14;8(6):e66866. doi: 10.1371/journal.pone.0066866. Print 2013.
Cervical cancer is caused by high-risk, cancer-causing human papillomaviruses (HPV) and is the second highest cause of cancer deaths in women globally. The majority of cervical cancers express well-characterized HPV oncogenes, which are potential targets for immunotherapeutic vaccination. Here we develop a rabbit haemorrhagic disease virus (RHDV) virus-like particle (VLP)-based vaccine designed for immunotherapy against HPV16 positive tumours. An RHDV-VLP, modified to contain the universal helper T cell epitope PADRE and decorated with an MHC I-restricted peptide (aa 48-57) from the HPV16 E6, was tested for its immunotherapeutic efficacy against the TC-1 HPV16 E6 and E7-expressing tumour in mice. The E6-RHDV-VLP-PADRE was administered therapeutically for the treatment of a pre-existing TC-1 tumour and was delivered with antibodies either to deplete regulatory T cells (anti-CD25) or to block T cell suppression mediated through CTLA-4. As a result, the tumour burden was reduced by around 50% and the median survival time of mice to the humane endpoint was almost doubled the compared to controls. The incorporation of PADRE into the RHDV-VLP was necessary for an E6-specific enhancement of the anti-tumour response and the co-administration of the immune modifying antibodies contributed to the overall efficacy of the immunotherapy. The E6-RHDV-VLP-PADRE shows immunotherapeutic efficacy, prolonging survival for HPV tumour-bearing mice. This was enhanced by the systemic administration of immune-modifying antibodies that are commercially available for use in humans. There is potential to further modify these particles for even greater efficacy in the path to development of an immunotherapeutic treatment for HPV precancerous and cancer stages.
宫颈癌是由高危致癌型人乳头瘤病毒（HPV）引起的，是全球女性癌症死亡的第二大主要原因。大多数宫颈癌表达特征明确的 HPV 致癌基因，这些基因是免疫治疗疫苗接种的潜在靶点。在这里，我们开发了一种基于兔出血症病毒（RHDV）病毒样颗粒（VLPs）的疫苗，旨在用于针对 HPV16 阳性肿瘤的免疫治疗。一种 RHDV-VLP 被修饰以包含通用辅助 T 细胞表位 PADRE，并被 HPV16 E6 的 MHC I 限制性肽（aa48-57）修饰，用于测试其对 TC-1 HPV16 E6 和 E7 表达肿瘤的免疫治疗功效在小鼠中。E6-RHDV-VLP-PADRE 用于治疗已存在的 TC-1 肿瘤，并与抗体一起给药，以耗尽调节性 T 细胞（抗 CD25）或阻断通过 CTLA-4 介导的 T 细胞抑制。结果，肿瘤负担减少了约 50%，与对照组相比，小鼠达到人道终点的中位生存时间几乎翻了一番。PADRE 掺入 RHDV-VLP 对于 E6 特异性增强抗肿瘤反应是必要的，并且免疫修饰抗体的共同给药有助于免疫治疗的整体疗效。E6-RHDV-VLP-PADRE 显示出免疫治疗功效，延长了 HPV 肿瘤小鼠的存活时间。通过系统给予可商购用于人类的免疫调节抗体，增强了这种功效。有可能进一步修饰这些颗粒，以在开发针对 HPV 癌前和癌症阶段的免疫治疗方法的道路上获得更高的疗效。
