Interleukin 12 secretion enhances antitumor efficacy of oncolytic herpes simplex viral therapy for colorectal cancer
Interleukin 12 secretion enhances antitumor efficacy of oncolytic herpes simplex viral therapy for colorectal cancer
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DOI：
10.1097/00000658-200106000-00012
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发表时间：
2001-06-01
影响因子：
9
通讯作者：
Fong, Y
中科院分区：
文献类型：
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作者：
Bennett, JJ;Malhotra, S;Fong, Y
目的评价溶瘤单纯疱疹病毒（HSV）联合免疫调节治疗实验性结肠癌的策略。在体外和体内评估了溶瘤 HSV 重组 NV1023 和分泌白细胞介素 12 (IL-12) 的溶瘤 NV1042 病毒的抗肿瘤功效。背景数据摘要基因工程、复制条件、减毒 HSV 已显示出针对多种实体恶性肿瘤的溶瘤活性。治疗癌症的其他策略涉及使用病毒载体的免疫调节和细胞因子基因转移。这项研究通过将鼠 IL-12 基因插入具有复制能力的 HSV 中，结合了这两种策略。这种方法允许溶瘤疗法在肿瘤细胞内选择性复制并裂解肿瘤细胞，同时为宿主免疫系统提供招募和激活增强抗肿瘤效果所需的炎症细胞所需的细胞因子刺激。MethodsNV1023是一种基于野生型HSV-1 F毒株的多突变HSV。 NV1042是通过将mIL-12基因插入NV1023而产生的。首次显示了 NV1023 和 NV1042 在小鼠 CT26 结直肠癌细胞中的细胞毒性和病毒增殖作用。然后，感染 NV1042 的细胞显示出显着水平的 IL-12。使用实验性结肠癌侧腹模型，用高剂量和低剂量的 NV1023 或 NV1042 治疗小鼠，并随访治愈和肿瘤负荷减少。结果两种病毒均可在体外复制并杀死 CT26 细胞，两种病毒感染后均实现 100% 细胞毒性。只有 NV1042 可以产生 mIL-12。使用高病毒剂量在体内治疗动物的疗法显示 NV1023 和 NV1042 之间的疗效相同，每种病毒七分之五治愈。当病毒剂量降低时，只有产生细胞因子的NV1042病毒才能减轻肿瘤负荷并治愈动物的疾病。结论NV1023和NV1042都具有在较高剂量下杀死结肠癌细胞的溶瘤潜力。 NV1042 产生的细胞因子可能允许使用较低剂量的病毒疗法，而不会失去抗肿瘤功效。应进一步研究溶瘤病毒疗法和免疫调节策略的结合作为结肠癌的治疗方法。
ObjectiveTo assess the strategy of combining oncolytic herpes simplex virus (HSV) therapy with immunomodulatory therapy as treatment for experimental colon cancer. The oncolytic HSV recombinant NV1023 and the interleukin 12 (IL-12)-secreting oncolytic NV1042 virus were evaluated in vitro and in vivo with respect to antitumor efficacy.Summary Background DataGenetically engineered, replication-conditional, attenuated HSVs have shown oncolytic activity against a wide variety of solid malignancies. Other strategies for treating cancer have involved immunomodulation and cytokine gene transfer using viral vectors. This study has combined both of these strategies by inserting the murine IL-12 gene into a replication-competent HSV. This approach allows oncolytic therapy to replicate selectively within and lyse tumor cells while providing the host immune system with the cytokine stimulus necessary to recruit and activate inflammatory cells needed to enhance the antitumor effect.MethodsNV1023 is a multimutant HSV based on the wild-type HSV-1 F strain. NV1042 was created by insertion of the mIL-12 gene into NV1023. Cytotoxicity and viral proliferation of both NV1023 and NV1042 within murine CT26 colorectal cancer cells were first shown. Cells infected with NV1042 were then shown to produce significant levels of IL-12. Using an experimental flank model of colon cancer, mice were treated with both high and low doses of NV1023 or NV1042 and were followed up for both cure and reduction in tumor burden.ResultsBoth viruses could replicate within and kill CT26 cells in vitro, with 100% cytotoxicity achieved after infection by either virus. Only NV1042 could produce mIL-12. Therapy using high viral doses to treat animals in vivo showed equal efficacy between NV1023 and NV1042, with five of seven cures for each virus. When viral doses were lowered, only the cytokine-producing NV1042 virus could reduce tumor burden and cure animals of their disease.ConclusionsBoth NV1023 and NV1042 have the oncolytic potential to kill colon cancer cells at higher doses. Cytokine production by NV1042 may allow lower doses of viral therapy to be used without losing antitumor efficacy. The combination of oncolytic viral therapy and immunomodulatory strategies should be further investigated as treatment for colon cancer.