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.

中文翻译：

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通过慢病毒疫苗彻底根除临床前人乳头瘤病毒诱发的肿瘤

人乳头瘤病毒 (HPV) 感染是所有宫颈癌以及多种口咽癌和肛门生殖器癌的病因。目前可用的 HPV 疫苗可诱导中和抗体，对已形成的肿瘤没有治疗作用。在这里，我们开发了一种针对 HPV 诱导的肿瘤的免疫肿瘤疗法，其基于编码 HPV16 和 18 基因型的早期 E6 和 E7 癌蛋白解毒形式的非整合慢病毒载体，即“Lenti-HPV-07”。对携带 HPV 诱导肿瘤的小鼠进行单次肌肉注射 Lenti-HPV-07，可实现 100% 动物的肿瘤完全根除，并且对肺转移也有效。这种效应与 CD8 ⁺ T 细胞诱导和肿瘤微环境的深刻重塑相关。在接种疫苗的小鼠的肿瘤内浸润中，存在大量激活的效应子、驻留记忆和转录因子 T 细胞因子-1 (TCF-1) ⁺ “干细胞样”CD8 ⁺ T 细胞与完整的肿瘤相关根除。Lenti-HPV-07 诱导的免疫力是持久的，并在后期重新攻击后阻止肿瘤生长，模拟肿瘤复发。Lenti-HPV-07 疗法与抗检查点抑制疗法具有协同作用，因此显示出作为针对 HPV 介导的恶性肿瘤的免疫肿瘤疗法的前景。