胶质母细胞瘤(GBM)是最致命的癌症之一,使用标准治疗(手术,辐射,和化疗),几十年来没有显著延长。GBM表现出显著的细胞异质性,先端有胶质母细胞瘤干细胞样细胞(GSC)。GSC是具有自我更新能力的GBM细胞亚群,区分,启动肿瘤形成,并操纵肿瘤微环境(TME)。GSC不再被认为是具有特异性标志物的静态细胞群,但在表型上和驱动肿瘤异质性和治疗抗性方面是相当灵活的。鉴于这些特点,它们是GBM治疗成功的关键目标。溶瘤病毒,特别是溶瘤单纯疱疹病毒(oHSV),具有许多治疗属性,并且是靶向GSC的有前途的药物。oHSV经过基因工程改造,可以选择性地在癌细胞中复制并杀死癌细胞,包括GSC,但不是正常细胞。此外,oHSV可以诱导抗肿瘤免疫反应,并与其他疗法协同作用,比如化疗,DNA修复抑制剂,免疫检查点抑制剂,以增强治疗效果并减少部分负责化学和放射性抗性的GSC群体。在这里,我们概述了GSC,不同OHSV的活动,临床试验结果,以及提高疗效的组合策略,包括OHSV的治疗武装。在整个过程中,治疗重点将放在GSCs和专门针对这些细胞的研究上.最近的临床试验和oHSVG47Δ在日本对复发性神经胶质瘤患者的批准证明了oHSV治疗的有效性和前景。
Glioblastoma (GBM) is one of the most lethal cancers, having a poor prognosis and a median survival of only about 15 months with standard treatment (surgery, radiation, and chemotherapy), which has not been significantly extended in decades. GBM demonstrates remarkable cellular heterogeneity, with glioblastoma stem-like cells (GSCs) at the apex. GSCs are a subpopulation of GBM cells that possess the ability to self-renew, differentiate, initiate tumor formation, and manipulate the tumor microenvironment (TME). GSCs are no longer considered a static population of cells with specific markers but are quite flexible phenotypically and in driving tumor heterogeneity and therapeutic resistance. In light of these features, they are a critical target for successful GBM therapy. Oncolytic viruses, in particular oncolytic herpes simplex viruses (oHSVs), have many attributes for therapy and are promising agents to target GSCs. oHSVs are genetically-engineered to selectively replicate in and kill cancer cells, including GSCs, but not normal cells. Moreover,
oHSV can induce anti-tumor immune responses and synergize with other therapies, such as chemotherapy, DNA repair inhibitors, and immune checkpoint inhibitors, to potentiate treatment effects and reduce GSC populations that are partly responsible for chemo- and radio-resistance. Herein, we present an overview of GSCs, activity of different oHSVs, clinical trial results, and combination strategies to enhance efficacy, including therapeutic arming of
oHSV. Throughout, the therapeutic focus will be on GSCs and studies specifically targeting these cells. Recent clinical trials and approval of
oHSV G47Δ in Japan for patients with recurrent glioma demonstrate the efficacy and promise of
oHSV therapy.