Eradication of solid human breast tumors in nude mice with an intravenously injected light-emitting oncolytic vaccinia virus
Eradication of solid human breast tumors in nude mice with an intravenously injected light-emitting oncolytic vaccinia virus
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DOI：
10.1158/0008-5472.can-07-0146
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发表时间：
2007-10-15
期刊：
影响因子：
11.2
通讯作者：
Szalay, Aladar A.
中科院分区：
文献类型：
--
作者：
Zhang, Qian;Yu, Yong A.;Szalay, Aladar A.
以前，我们报道了一种携带发光融合基因的重组牛痘病毒（VACV）进入，复制，并揭示了小鼠肿瘤的位置。通过在VACV基因组的F14.5L、J2 R和A56 R位点分别插入3个表达盒（分别编码海肾酶-水母绿色荧光蛋白融合蛋白、β-半乳糖苷酶和β-葡萄糖醛酸酶），构建了一种新的VACV，GLV-1h 68，可作为诊断和治疗的同时性药物。将GLV-1h 68（每只小鼠1 × 107空斑形成单位）静脉注射到已建立（类似于300-500 mm（3））s.c.使用GI-101 A人乳腺肿瘤来评价其毒性、肿瘤靶向特异性和溶瘤功效。GLV-1h 68与其亲本LIVP菌株相比显示出增强的肿瘤靶向特异性和大大降低的毒性。在95%的受试小鼠中，由GLV 1h 68定殖的肿瘤表现出生长、抑制和消退阶段，随后在130天内肿瘤根除。基于减少的光发射，在真实的时间内监测活体动物中的肿瘤消退，因此证明了组合的溶瘤病毒介导的肿瘤诊断和治疗系统的概念。基于小鼠特异性平台的消退肿瘤的转录谱分析揭示了与免疫防御激活一致的基因表达特征，包括IFN刺激的基因（STAT-1和IRF-7）、细胞因子、趋化因子和先天免疫效应子功能。这些发现表明，免疫激活可能与病毒溶瘤联合收割机在该模型中诱导肿瘤根除，为设计用于人类癌症的溶瘤病毒疗法提供了新的视角。[Cancer Res 2007;67（20）：10038-46]
Previously, we reported that a recombinant vaccinia virus (VACV) carrying a light-emitting fusion gene enters, replicates in, and reveals the locations of tumors in mice. A new recombinant VACV, GLV-1h68, as a simultaneous diagnostic and therapeutic agent, was constructed by inserting three expression cassettes (encoding Renilla luciferase-Aequorea green fluorescent protein fusion, beta-galactosidase, and beta-glucuronidase) into the F14.5L, J2R (encoding thymidine kinase) and A56R (encoding hemagglutinin) loci of the viral genome, respectively. I.v. injections of GLV-1h68 (I X 107 plaqueforming unit per mouse) into nude mice with established (similar to 300-500 mm(3)) s.c. GI-101A human breast tumors were used to evaluate its toxicity, tumor targeting specificity, and oncolytic efficacy. GLV-1h68 showed an enhanced tumor targeting specificity and much reduced toxicity compared with its parental LIVP strains. The tumors colonized by GLV1h68 exhibited growth, inhibition, and regression phases followed by tumor eradication within 130 days in 95% of the mice tested. Tumor regression in live animals was monitored in real time based on decreasing light emission, hence demonstrating the concept of a combined oncolyticvirusmediated tumor diagnosis and therapy system. Transcriptional profiling of regressing tumors based on a mouse-specific platform revealed gene expression signatures consistent with immune defense activation, inclusive of IFN-stimulated genes (STAT-1 and IRF-7), cytokines, chemokines, and innate immune effector function. These findings suggest that immune activation may combine with viral oncolysis to induce tumor eradication in this model, providing a novel perspective for the design of oncolytic viral therapies for human cancers. [Cancer Res 2007;67(20):10038-46]