肿瘤细胞治疗研究
英文原题：Development and preclinical evaluation of KDTV001, an adenovirus 5-vectored trivalent HPV therapeutic vaccine targeting HPV16/18/52.
KDTV001，一种靶向HPV16/18/52的腺病毒5载体三价治疗性疫苗，在多种临床前模型中展现出强效免疫原性、显著抗肿瘤疗效及长期保护性免疫，为治疗HPV相关恶性肿瘤的临床转化铺平了道路。
持续高危型HPV感染（如HPV16/18/52）与宫颈癌的发生直接相关，因此有必要开发有效的多靶点治疗性疫苗。
我们开发了KDTV001，这是一种非复制型腺病毒5载体三价疫苗，编码来自HPV16/18/52的工程化E6/E7癌蛋白。其免疫原性在C57BL/6、CD1、HLA转基因小鼠、SD大鼠以及人DC-T细胞共培养系统中进行了评估。评估包括IFN-γ ELISpot、流式细胞术、肿瘤攻击/再攻击、淋巴细胞的单细胞RNA/TCR测序（scRNA/TCR-seq）以及免疫细胞清除。
KDTV001在多种模型中展现出强效的临床前疗效，在免疫健全小鼠和HLA转基因小鼠中诱导了强效的免疫应答和交叉反应性应答。scRNA/TCR-seq揭示KDTV001重塑了肿瘤微环境，增加了细胞毒性CD8+ T细胞，并促进了T细胞克隆扩增和分化。单次给药使60-80%的小鼠实现TC-1肿瘤完全消退，并具有持久保护作用（>200天）。优化加强免疫接种方案减轻了预存载体免疫对KDTV001免疫原性的影响。通过HLA-A转基因小鼠和PBMC共培养中的抗原特异性T细胞活化和扩增，证实了其与人类的相关性。
BACKGROUND: Persistent high-risk HPV infections (e.g., HPV16/18/52) are directly linked to cervical cancer development, thus necessitating the development of effective multi-target therapeutic vaccines. METHODS: We developed KDTV001, a non-replicating adenovirus 5-vectored trivalent vaccine encoding engineered E6/E7 oncoproteins from HPV16/18/52. Its immunogenicity was evaluated in C57BL/6, CD1, HLA-transgenic mice, SD rats, and a human DC-T cell co-culture system. Assessments included IFN-γ ELISpot, flow cytometry, tumour challenge/rechallenge, single-cell RNA/TCR sequencing (scRNA/TCR-seq) of lymphocytes, and immune cell depletion. FINDINGS: KDTV001 demonstrated robust preclinical efficacy across multiple models, eliciting potent immune and cross-reactive responses in immunocompetent and HLA-transgenic mice. scRNA/TCR-seq revealed KDTV001 remodelled the tumour microenvironment, increasing cytotoxic CD8 + T cells and promoting T cell clonal expansion and differentiation. A single dose induced complete TC-1 tumour regression in 60-80% of mice with durable protection (>200 days). Optimising the booster immunisation schedule mitigated the impact of pre-existing vector immunity on the immunogenicity of KDTV001. Human relevance was confirmed through antigen-specific T-cell activation and expansion in HLA-A transgenic mice and PBMC co-cultures. INTERPRETATION: KDTV001, the adenovirus 5-vectored trivalent therapeutic vaccine targeting HPV16/18/52, demonstrates potent immunogenicity, significant antitumour efficacy, and long-term protective immunity across diverse preclinical models, paving the way for clinical translation in treating HPV-associated malignancies. FUNDING: This study was funded by the Noncommunicable Chronic Diseases-National Science and Technology Major Project of China (Nos.2025ZD0544101), the Hubei Provincial Science and Technology Major Project of China (Nos.2023BCA004), and the National Clinical Research Center for Gynaecological Diseases Special Fund of China (Nos.2025LCPT01).
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