Efficacy of a Third-Generation Oncolytic Herpes Virus G47Δ in Advanced Stage Models of Human Gastric Cancer
Efficacy of a Third-Generation Oncolytic Herpes Virus G47Δ in Advanced Stage Models of Human Gastric Cancer
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DOI：
10.1016/j.omto.2020.03.022
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发表时间：
2020-06-26
期刊：
影响因子：
--
通讯作者：
Todo, Tomoki
中科院分区：
文献类型：
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作者：
Sugawara, Kotaro;Iwai, Miwako;Todo, Tomoki
进展期胃癌，尤其是伴有腹膜播散的硬化性胃癌，对传统治疗方法仍然难以奏效。G47 Delta是第三代溶瘤型单纯疱疹病毒1型，是一种有吸引力的实体癌新治疗剂。在这项研究中，我们研究了G47 Delta对人胃癌的治疗潜力。在体外，G47 Delta在9个被测试的人胃癌细胞系中表现出良好的细胞病变效应和复制能力。在体内，瘤内接种G47 Delta(2×10(5)或1×10(6)空斑形成单位[PFU])显著抑制皮下肿瘤(MKN45、MKN74和44As3)的生长。为了评价G47 Delta对进展期胃癌模型的疗效，我们建立了人硬化性胃癌的原位肿瘤模型和腹膜扩散模型(MKN45-Luc和44As3Luc)，它们具有模拟顽固性硬化性胃癌患者的特征。在临床相关模型中，G47 Delta(1×10(6)PFU)无论是在肿瘤内还是在腹膜内给药都是持续有效的。值得注意的是，G47 Delta腹腔注射很容易分布到播散性肿瘤中，并有选择地在其中复制。此外，对皮下肿瘤中肿瘤浸润性细胞的流式细胞术分析显示，G47 Delta瘤内注射显著减少M2巨噬细胞，而增加ML巨噬细胞和自然杀伤(NK)细胞。这些发现表明G47 Delta用于治疗人胃癌，包括硬化性胃癌和晚期胃癌是有效的。
Advanced gastric cancer, especially scirrhous gastric cancer with peritoneal dissemination, remains refractory to conventional therapies. G47 Delta, a third-generation oncolytic herpes simplex virus type 1, is an attractive novel therapeutic agent for solid cancer. In this study, we investigated the therapeutic potential of G47 Delta for human gastric cancer. In vitro, G47 Delta showed good cytopathic effects and replication capabilities in nine human gastric cancer cell lines tested. In vivo, intratumoral inoculations with G47 Delta (2 x 10(5) or 1 x 10(6) plaqueforming units [PFU]) significantly inhibited the growth of subcutaneous tumors (MKN45, MKN74, and 44As3). To evaluate the efficacy of G47 Delta for advanced-stage models of gastric cancer, we generated an orthotopic tumor model and peritoneal dissemination models of human scirrhous gastric cancer (MKN45-luc and 44As3Luc), which have features mimicking intractable scirrhous cancer patients. G47 Delta (1 x 10(6) PFU) was constantly efficacious whether administered intratumorally or intraperitoneally in the clinically relevant models. Notably, G47 Delta injected intraperitoneally readily distributed to, and selectively replicated in, disseminated tumors. Furthermore, flow cytometric analyses of tumor-infiltrating cells in subcutaneous tumors revealed that intratumoral G47 Delta injections markedly decreased M2 macrophages while increasing Ml macrophages and natural killer (NK) cells. These findings indicate the usefulness of G47 Delta for treating human gastric cancer, including scirrhous gastric cancer and the ones in advanced stages.