PT  - JOURNAL ARTICLE
AU  - Wildeman, Maarten A.
AU  - Novalić, Zlata
AU  - Verkuijlen, Sandra A.W.M.
AU  - Juwana, Hedy
AU  - Huitema, Alwin D.R.
AU  - Tan, I. Bing
AU  - Middeldorp, Jaap M.
AU  - de Boer, Jan Paul
AU  - Greijer, Astrid E.
TI  - Cytolytic Virus Activation Therapy for Epstein-Barr Virus–Driven Tumors
AID  - 10.1158/1078-0432.CCR-12-0574
DP  - 2012 Sep 15
TA  - Clinical Cancer Research
PG  - 5061--5070
VI  - 18
IP  - 18
4099  - http://clincancerres.aacrjournals.org/content/18/18/5061.short
4100  - http://clincancerres.aacrjournals.org/content/18/18/5061.full
SO  - Clin Cancer Res2012 Sep 15; 18
AB  - Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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. Clin Cancer Res; 18(18); 5061–70. ©2012 AACR.