Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Via S. Pansini, 5, 80131, Naples, Italy.
CEINGE Biotecnologie Avanzate S.C.aR.L., Via G. Salvatore 486, 80145, Naples, Italy.
Sci Rep. 2020 Mar 9;10(1):4307. doi: 10.1038/s41598-020-61275-w.
Oncolytic virotherapy is emerging as a promising therapeutic option for solid tumours. Several oncolytic vectors in clinical testing are based on attenuated viruses; thus, efforts are being taken to develop a new repertoire of oncolytic viruses, based on virulent viral genomes. This possibility, however, raises concerns dealing with the safety features of the virulent phenotypes. We generated a double regulated Herpes simplex type-1 virus (HSV-1), in which tumour cell restricted replicative potential was combined to selective entry via ERBB2 receptor retargeting. The transcriptional control of the viral alpha4 gene encoding for the infected cell protein-4 (ICP4) by the cellular Survivin/BIRC5 promoter conferred a tumour cell-restricted replicative potential to a virulent HSV-1 genome. The combination of the additional ERBB2 retargeting further improved the selectivity for tumour cells, conferring to the double regulated virus a very limited ability to infect and propagate in non-cancerous cells. Accordingly, a suitable replicative and cytotoxic potential was maintained in tumour cell lines, allowing the double regulated virus to synergize in vivo with immune checkpoint (anti-PD-1) blockade in immunocompetent mice. Thus, restricting the replicative spectrum and tropism of virulent HSV-1 genomes by combination of conditional replication and retargeting provides an improved safety, does not alter the oncolytic strength, and is exploitable for its therapeutic potential with immune checkpoint blockade in cancer.
溶瘤病毒治疗法正逐渐成为治疗实体肿瘤的一种有前途的治疗选择。目前正在临床试验中的几种溶瘤病毒载体都是基于减毒病毒；因此，人们正在努力开发一系列新的溶瘤病毒，这些病毒基于毒性病毒基因组。然而，这种可能性引发了人们对毒性表型的安全特性的关注。我们生成了一种双重调控的单纯疱疹病毒 1 型（HSV-1），其中肿瘤细胞受限的复制能力与通过 ERBB2 受体重新靶向的选择性进入相结合。通过细胞 Survivin/BIRC5 启动子对编码感染细胞蛋白 4（ICP4）的病毒 alpha4 基因进行转录控制，赋予了毒性 HSV-1 基因组以肿瘤细胞受限的复制能力。通过额外的 ERBB2 重新靶向的结合，进一步提高了对肿瘤细胞的选择性，使双调控病毒在非癌细胞中感染和繁殖的能力非常有限。因此，在肿瘤细胞系中保持了适当的复制和细胞毒性潜力，使双调控病毒能够在免疫功能正常的小鼠中与免疫检查点（抗 PD-1）阻断协同作用。因此，通过条件性复制和靶向相结合来限制毒性 HSV-1 基因组的复制谱和趋向性，可提高安全性，不会改变溶瘤强度，并可利用其与癌症的免疫检查点阻断的治疗潜力。
