Carrier cell-based delivery of replication-competent HSV-1 mutants enhances antitumor effect for ovarian cancer.
Carrier cell-based delivery of replication-competent HSV-1 mutants enhances antitumor effect for ovarian cancer.
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DOI：
10.1038/cgt.2010.53
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发表时间：
2011-02
影响因子：
6.4
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中科院分区：
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能够肿瘤选择性复制和细胞溶解的溶瘤病毒已经显示出作为癌症治疗剂的早期前景。我们已经开发了复制能力减毒单纯疱疹病毒1型（HSV-1）突变体，命名为HF 10和Hh 101，已被评估其溶瘤活性。然而，宿主免疫系统仍然是在临床环境中有效腹膜内施用这些病毒的显著障碍。在这项研究中，我们研究了使用这些HSV-1突变体作为溶瘤剂对卵巢癌和使用人腹膜间皮细胞（MC）作为载体细胞腹腔内治疗。MCs被HSV-1突变体有效感染，并且当在存在或不存在HSV抗体的情况下与癌细胞共培养时，装载HSV-1突变体的MCs充分引起细胞杀伤。在卵巢癌的小鼠异种移植模型中，与单独注射病毒相比，注射受感染的载体细胞导致肿瘤体积显著减小，存活期延长。我们的研究结果表明，复制能力减毒HSV-1发挥了有效的溶瘤作用，卵巢癌，这可能会进一步加强利用载体细胞传递系统，基于病毒载量的扩增，并可能避免中和抗体。
Oncolytic viruses capable of tumor-selective replication and cytolysis have shown early promise as cancer therapeutics. We have developed replication-competent attenuated herpes simplex virus type 1 (HSV-1) mutants, named HF10 and Hh101, which have been evaluated for their oncolytic activities. However, the host immune system remains a significant obstacle to effective intraperitoneal administration of these viruses in the clinical setting. In this study, we investigated the use of these HSV-1 mutants as oncolytic agents against ovarian cancer and the use of human peritoneal mesothelial cells (MCs) as carrier cells for intraperitoneal therapy. MCs were efficiently infected with HSV-1 mutants, and MCs loaded with HSV-1 mutants caused cell killing adequately when cocultured with cancer cells in the presence or absence of HSV antibodies. In a mouse xenograft model of ovarian cancer, the injection of infected carrier cells led to a significant reduction of tumor volume and prolonged survival in comparison with the injection of virus alone. Our results indicate that replication-competent attenuated HSV-1 exerts a potent oncolytic effect on ovarian cancer, which may be further enhanced by the utilization of a carrier cell delivery system, based on amplification of viral load and possibly on avoidance of neutralizing antibodies.