通过使用活病毒进行全身免疫诱导抗病毒先天性免疫，可用于积极影响治疗性疫苗的反应。我们之前已经证明了使用非复制MVA编码CD40配体（CD40L）进行全身免疫可增强先天免疫细胞激活和功能，触发不同的小鼠肿瘤模型中的强大的抗肿瘤CD8+ T细胞反应。当与针对肿瘤的抗体结合时，抗肿瘤疗效增强。在这里，我们报道了TAEK-VAC-HerBy（TVH）的开发，这是一种基于非复制MVA-BN病毒载体的第一类人类肿瘤抗体增强杀伤（TAEK）疫苗。它编码人类CD40L的膜结合形式，HER2和转录因子Brachyury。TVH旨在与针对肿瘤的抗体组合治疗HER2或Brachyury表达的癌症患者。为了防止可能的致癌活性，以及防止疫苗编码HER2与单克隆抗体曲妥珠单抗和佩珠单抗结合，对HER2进行了遗传修饰。Brachyury进行了遗传修饰，以防止蛋白质的核定位，从而抑制其转录活性。在TVH中编码的CD40L增强了体外人类白细胞的激活和细胞因子分泌。最后，在非人类灵长类动物中静脉注射TVH在重复剂量毒性研究中证明具有免疫原性和安全性。所呈现的非临床数据突出了TVH作为一种正在接受临床研究的第一类免疫治疗疫苗平台。©2023作者。

The induction of antiviral innate immunity by systemic immunization with live virus can be employed to positively impact the response to therapeutic vaccination. We previously demonstrated that systemic immunization with a non-replicating MVA encoding CD40 ligand (CD40L) enhances innate immune cell activation and function, and triggers potent antitumor CD8+ T cell responses in different murine tumor models. Antitumor efficacy was increased when combined with tumor targeting antibodies. Here we report the development of TAEK-VAC-HerBy (TVH), a first-in-class human tumor antibody enhanced killing (TAEK) vaccine based on the non-replicating MVA-BN viral vector. It encodes the membrane bound form of human CD40L, HER2 and the transcription factor Brachyury. TVH is designed for therapeutic use in HER2- or Brachyury-expressing cancer patients in combination with tumor targeting antibodies. To preclude possible oncogenic activities in infected cells and to prevent binding of vaccine-encoded HER2 by monoclonal antibodies trastuzumab and pertuzumab, genetic modifications of HER2 were introduced in the vaccine. Brachyury was genetically modified to prevent nuclear localization of the protein thereby inhibiting its transcriptional activity. CD40L encoded in TVH enhanced human leukocyte activation and cytokine secretion in vitro. Lastly, TVH intravenous administration to non-human primates was proven immunogenic and safe in a repeat-dose toxicity study. Nonclinical data presented here highlight TVH as a first-in-class immunotherapeutic vaccine platform currently under clinical investigation.© 2023. The Author(s).