title: Cytolytic virus activation therapy for Epstein-Barr virus-driven tumors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors: Departments of Head and Neck Oncology and Surgery and Medical Oncology, The Netherlands.
authors: Maarten A
authors: MA
authors: Wildeman
authors: Zlata
authors: Z
authors: Novalic
authors: Sandra A W M
authors: SA
authors: Verkuijlen
authors: Hedy
authors: H
authors: Juwana
authors: Alwin D R
authors: AD
authors: Huitema
authors: I Bing
authors: IB
authors: Tan
authors: Jaap M
authors: JM
authors: Middeldorp
authors: Jan Paul
authors: JP
authors: de Boer
authors: Astrid E
authors: AE
authors: Greijer
mesh_terms: D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D002277:Carcinoma; D045744:Cell Line, Tumor; D004279:DNA, Viral / Q000235:genetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D005260:Female; D004854:Herpesvirus 4, Human / Q000187:drug effects* / Q000276:immunology / Q000472:pathogenicity; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D009367:Neoplasm Staging; D016896:Treatment Outcome; D014635:Valproic Acid / Q000008:administration & dosage; D019562:Viral Load; D014775:Virus Activation / Q000187:drug effects*; D000093542:Gemcitabine
chemical_list: D000914:Antibodies, Viral; D004279:DNA, Viral; D007074:Immunoglobulin G; D003841:Deoxycytidine; D014635:Valproic Acid; D000093542:Gemcitabine