Preclinical And Clinical Development Of Oncolytic Adenovirus For The Treatment Of Malignant Glioma

IF 6.7
Juri Kiyokawa, H. Wakimoto
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引用次数: 44

Abstract

Abstract Replication conditional oncolytic human adenovirus has long been considered a promising biological therapeutic to target high-grade gliomas (HGG), a group of essentially lethal primary brain cancer. The last decade has witnessed initiation and some completion of a number of Phase I and II clinical investigations of oncolytic adenovirus for HGG in the US and Europe. Results of these trials in patients are pivotal for not only federal approval but also filling an existing knowledge gap that primarily derives from the stark differences in permissivity to human adenovirus between humans and preclinical mouse models. DNX-2401 (Delta-24-RGD), the current mainstream oncolytic adenovirus with modifications in E1A and the fiber, has been shown to induce impressive objective response and long-term survival (>3 years) in a fraction of patients with recurrent HGG. Responders exhibited initial enlargement of the treated lesions for a few months post treatment, followed by shrinkage and near complete resolution. In accord with preclinical research, post-treatment specimens revealed virus-mediated alteration of the immune tumor microenvironment as evidenced by infiltration of CD8+ T cells and M1-polarized macrophages. These findings are encouraging and together with further information from ongoing studies have a potential to make oncolytic adenovirus a viable option for clinical management of HGG. This review deals with this timely topic; we will describe both preclinical and clinical development of oncolytic adenovirus therapy for HGG, summarize updated knowledge on clinical trials and discuss challenges that the field currently faces.
溶瘤腺病毒治疗恶性胶质瘤的临床前和临床进展
复制条件溶瘤人腺病毒长期以来被认为是一种很有前途的生物疗法,用于治疗高级别胶质瘤(HGG),这是一组本质上致命的原发性脑癌。在过去的十年中,美国和欧洲已经开始并完成了许多溶瘤腺病毒治疗HGG的I期和II期临床研究。这些患者试验的结果不仅对联邦政府的批准至关重要,而且还填补了现有的知识空白,这主要源于人类和临床前小鼠模型之间对人类腺病毒的容受性存在明显差异。DNX-2401 (Delta-24-RGD)是目前主流的溶瘤腺病毒,在E1A和纤维中进行修饰,已被证明可在部分复发性HGG患者中诱导令人印象深刻的客观反应和长期生存期(3年)。应答者在治疗后几个月表现出治疗病变的初始扩大,随后缩小并接近完全消退。与临床前研究一致,治疗后标本显示病毒介导的肿瘤免疫微环境改变,表现为CD8+ T细胞和m1极化巨噬细胞的浸润。这些发现令人鼓舞,并与正在进行的研究的进一步信息一起,有可能使溶瘤腺病毒成为HGG临床治疗的可行选择。这篇评论讨论了这个及时的话题;我们将描述溶瘤腺病毒治疗HGG的临床前和临床发展,总结临床试验的最新知识,并讨论该领域目前面临的挑战。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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