Department of Urology, Kyorin University School of Medicine, Tokyo, Japan.
Division of Innovative Cancer Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Cancer Sci. 2021 Aug;112(8):3293-3301. doi: 10.1111/cas.14981. Epub 2021 Jun 9.
Oncolytic virus therapy has emerged as a promising treatment option against cancer. To date, oncolytic viruses have been developed for malignant tumors, but the need for this new therapeutic modality also exists for benign and slow-growing tumors. G47∆ is an oncolytic herpes simplex virus type 1 (HSV-1) with an enhanced replication capability highly selective to tumor cells due to genetically engineered, triple mutations in the γ34.5, ICP6 and α47 genes. To create a powerful, but safe oncolytic HSV-1 that replicates efficiently in tumors regardless of growth speed, we used a bacterial artificial chromosome system that allows a desired promoter to regulate the expression of the ICP6 gene in the G47∆ backbone. Restoration of the ICP6 function in a tumor-specific manner using the hTERT promoter led to a highly capable oncolytic HSV-1. T-hTERT was more efficacious in the slow-growing OS-RC-2 and DU145 tumors than the control viruses, while retaining a high efficacy in the fast-growing U87MG tumors. The safety features are also retained, as T-hTERT proved safe when inoculated into the brain of HSV-1 sensitive A/J mice. This new technology should facilitate the use of oncolytic HSV-1 for all tumors irrespective of growth speed.
溶瘤病毒治疗已成为癌症治疗的一种有前途的选择。迄今为止，已经开发出用于恶性肿瘤的溶瘤病毒，但这种新的治疗方式也需要用于良性和生长缓慢的肿瘤。G47∆ 是一种具有增强复制能力的溶瘤单纯疱疹病毒 1（HSV-1），由于在 γ34.5、ICP6 和 α47 基因中进行了基因工程三重突变，因此对肿瘤细胞具有高度选择性。为了创建一种强大但安全的溶瘤 HSV-1，使其能够在无论肿瘤生长速度如何的情况下高效复制，我们使用了细菌人工染色体系统，该系统允许所需的启动子调节 G47∆ 骨架中 ICP6 基因的表达。使用端粒酶逆转录酶（hTERT）启动子以肿瘤特异性方式恢复 ICP6 功能，导致具有高度能力的溶瘤 HSV-1。与对照病毒相比，T-hTERT 在生长缓慢的 OS-RC-2 和 DU145 肿瘤中更有效，而在快速生长的 U87MG 肿瘤中仍保持高疗效。安全性特征也得到保留，因为当将 T-hTERT 接种到 HSV-1 敏感的 A/J 小鼠的大脑中时，它被证明是安全的。这项新技术应该促进使用溶瘤 HSV-1 治疗所有肿瘤，而与肿瘤生长速度无关。
