Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China; Henan Key Laboratory of Stem Cell Differentiation and Modification, Henan Provincial People's Hospital, 7 Weiwu Road, Zhengzhou, Henan 450003, China.
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China.
Mol Ther. 2019 Nov 6;27(11):1906-1918. doi: 10.1016/j.ymthe.2019.07.019. Epub 2019 Aug 5.
Oncolytic viruses are an excellent platform for developing effective strategies in cancer immunotherapy. Several challenges remain in the use of viro-immunotherapy for cancer, such as the lack of costimulatory signals and negative regulation of immune checkpoints. In this study, we designed a novel adenovirus expressing a soluble fusion protein, programmed cell death protein 1 (PD-1)/CD137L, which contains the extracellular domains of PD-1 and CD137L at each terminus (Ad5-PC). Ad5-PC preserved the costimulatory activity of CD137L and facilitated the persistence of activated CD8 T cells. Ad5-PC induced strikingly increased antitumor activity in both ascitic and subcutaneous hepatocellular carcinoma (HCC) tumor models, with 70% and 60% long-term cure rates, respectively. The improved antitumor effect of Ad5-PC was attributed to the sustained high-level lymphocyte activation and interferon (IFN)-γ production in the tumor microenvironment, and was essentially dependent on CD8 T cells rather than natural killer (NK) cells. Moreover, Ad5-huPC-expressing human soluble PD-1/CD137L fusion protein was effective in suppressing tumor growth and improving survival in a humanized mouse model. We confirmed that Ad5-PC induced tumor-specific and systematic protection against tumor rechallenges at both in situ and distant sites. Thus, Ad5-PC harnesses several distinct functions to efficiently overcome several major hurdles of viro-immunotherapy.
溶瘤病毒是开发癌症免疫治疗有效策略的优秀平台。在使用病毒免疫疗法治疗癌症方面，仍存在一些挑战，例如缺乏共刺激信号和免疫检查点的负调控。在这项研究中，我们设计了一种新型腺病毒，表达一种可溶性融合蛋白，程序性死亡蛋白 1（PD-1）/CD137L，其两端分别包含 PD-1 和 CD137L 的细胞外结构域（Ad5-PC）。Ad5-PC 保留了 CD137L 的共刺激活性，并促进了激活的 CD8 T 细胞的持续存在。Ad5-PC 在腹水和皮下肝癌（HCC）肿瘤模型中均显著增强了抗肿瘤活性，分别有 70%和 60%的长期治愈率。Ad5-PC 的抗肿瘤效果的改善归因于肿瘤微环境中持续高水平的淋巴细胞激活和干扰素（IFN）-γ产生，并且基本上依赖于 CD8 T 细胞而不是自然杀伤（NK）细胞。此外，表达人可溶性 PD-1/CD137L 融合蛋白的 Ad5-huPC 在人源化小鼠模型中有效抑制肿瘤生长并提高存活率。我们证实，Ad5-PC 诱导了针对原位和远处肿瘤再挑战的肿瘤特异性和系统性保护。因此，Ad5-PC 利用了几种不同的功能，有效地克服了病毒免疫治疗的几个主要障碍。
