人类乳头瘤病毒（HPV）感染是所有宫颈癌以及许多口咽部和肛门癌的原因。目前可用的HPV疫苗通过诱导中和抗体，对已建立的肿瘤没有治疗效果。在这里，我们基于非整合性慢病毒载体开发了一种针对HPV诱导肿瘤的免疫治疗方法，该载体编码HPV16和18基因型的早期E6和E7致癌蛋白的解毒形式，即“Lenti-HPV-07”。将Lenti-HPV-07单剂肌肉注射到患有已建立的HPV诱导肿瘤的小鼠中，可以使100%的动物完全消除肿瘤，并且对肺转移也有效。这种效果与CD8+T细胞的诱导和肿瘤微环境的深度重构相一致。在接种疫苗的小鼠的肿瘤内渗出物中，大量活化的效应子、驻留记忆和转录因子TCF-1+“干细胞样”CD8+T细胞的存在与完全消除肿瘤有关。Lenti-HPV-07诱导的免疫反应持久，并且在迟期再次挑战后可以防止肿瘤生长，模拟肿瘤复发。Lenti-HPV-07治疗与抗检查点抑制治疗协同作用，因此有望成为针对已建立的HPV介导恶性肿瘤的免疫治疗方法。© 2023年作者发表。根据CC BY 4.0协议发布。 Note: The above translation is simplified Chinese (中国简体).

Human papillomavirus (HPV) infections are the cause of all cervical and numerous oropharyngeal and anogenital cancers. The currently available HPV vaccines, which induce neutralizing antibodies, have no therapeutic effect on established tumors. Here, we developed an immuno-oncotherapy against HPV-induced tumors based on a non-integrative lentiviral vector encoding detoxified forms of the Early E6 and E7 oncoproteins of HPV16 and 18 genotypes, namely, "Lenti-HPV-07". A single intramuscular injection of Lenti-HPV-07 into mice bearing established HPV-induced tumors resulted in complete tumor eradication in 100% of the animals and was also effective against lung metastases. This effect correlated with CD8+ T-cell induction and profound remodeling of the tumor microenvironment. In the intra-tumoral infiltrates of vaccinated mice, the presence of large amounts of activated effector, resident memory, and transcription factor T cell factor-1 (TCF-1)+ "stem-like" CD8+ T cells was associated with full tumor eradication. The Lenti-HPV-07-induced immunity was long-lasting and prevented tumor growth after a late re-challenge, mimicking tumor relapse. Lenti-HPV-07 therapy synergizes with an anti-checkpoint inhibitory treatment and therefore shows promise as an immuno-oncotherapy against established HPV-mediated malignancies.© 2023 The Authors. Published under the terms of the CC BY 4.0 license.