Departments of Head and Neck Oncology and Surgery and Medical Oncology, The Netherlands.
Clin Cancer Res. 2012 Sep 15;18(18):5061-70. doi: 10.1158/1078-0432.CCR-12-0574. Epub 2012 Jul 3.
Nasopharyngeal carcinoma (NPC) is causally linked to Epstein-Barr virus (EBV) infection. Because all tumor cells carry EBV, the virus itself is a potential target for therapy. In these tumor cells, EBV hides in a latent state and expresses only a few non-immunogenic proteins for EBV maintenance and contributes to tumor growth. We developed a cytolytic virus activation (CLVA) therapy for NPC treatment, reactivating latent EBV, triggering immune recognition, and inducing susceptibility to antiviral therapy.
CLVA therapy combines gemcitabine (GCb) and valproic acid (VPA) for virus activation and tumor clearance with (val)ganciclovir (GCV) as the antiviral drug to block virus replication and kill proliferating virus-infected cells. CLVA treatment was optimized and validated in NPC cell lines and subsequently tested in 3 Dutch patients with NPC that was refractory to conventional treatment.
In NPC cell lines, both GCb and VPA can induce the lytic cycle of EBV. Their combination resulted in a strong synergistic effect. The addition of GCV resulted in higher cytotoxicity compared with chemotherapy alone, which was not observed in EBV-negative cells. CLVA therapy was analyzed in 3 patients with end-stage NPC. Patients developed increased levels of viral DNA in the circulation originating from apoptotic tumor cells, had disease stabilization, and experienced improved quality of life.
Our results in the initial CLVA-treated patients indicate that the therapy had a biological effect and was well tolerated with only moderate transient toxicity. This new virus-specific therapy could open a generic approach for treatment of multiple EBV-associated malignancies.
鼻咽癌（NPC）与 Epstein-Barr 病毒（EBV）感染有关。由于所有肿瘤细胞都携带 EBV，因此病毒本身是治疗的潜在靶点。在这些肿瘤细胞中，EBV 处于潜伏状态，只表达少数用于 EBV 维持和促进肿瘤生长的非免疫原性蛋白。我们开发了一种溶瘤病毒激活（CLVA）疗法来治疗 NPC，重新激活潜伏的 EBV，触发免疫识别，并诱导对抗病毒治疗的敏感性。
CLVA 疗法结合吉西他滨（GCb）和丙戊酸（VPA）用于病毒激活和肿瘤清除，并用缬更昔洛韦（GCV）作为抗病毒药物来阻断病毒复制并杀死增殖的病毒感染细胞。CLVA 治疗在 NPC 细胞系中进行了优化和验证，随后在 3 名对常规治疗耐药的 NPC 荷兰患者中进行了测试。
在 NPC 细胞系中，GCb 和 VPA 均可诱导 EBV 的裂解周期。它们的组合产生了强烈的协同作用。与单独化疗相比，添加 GCV 导致更高的细胞毒性，而在 EBV 阴性细胞中未观察到这种现象。CLVA 治疗在 3 名晚期 NPC 患者中进行了分析。患者循环中源自凋亡肿瘤细胞的病毒 DNA 水平升高，疾病稳定，生活质量提高。
我们在最初接受 CLVA 治疗的患者中的结果表明，该疗法具有生物学效应，并且仅具有中度短暂毒性，耐受性良好。这种新的病毒特异性疗法可能为治疗多种 EBV 相关恶性肿瘤开辟一种通用方法。
