Cytolytic virus activation therapy for Epstein-Barr virus-driventumors

Maarten A. Wildeman, Zlata Novalić, Sandra A.W.M. Verkuijlen, Hedy Juwana, Alwin D.R. Huitema, I. Bing Tan, Jaap M. Middeldorp, Jan Paul De Boer, Astrid E. Greijer

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72 Citaten (Scopus)


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.CLVAtherapy 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.

Originele taal-2Engels
Pagina's (van-tot)5061-5070
Aantal pagina's10
TijdschriftClinical Cancer Research
Nummer van het tijdschrift18
StatusGepubliceerd - 15 sep. 2012
Extern gepubliceerdJa


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