Cytolytic virus activation therapy for Epstein-Barr virus-driven tumors.

Abstract

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.

• Authors: Maarten A Wildeman, Zlata Novalic, Sandra A W M Verkuijlen, Hedy Juwana, Alwin D R Huitema, I Bing Tan, Jaap M Middeldorp, Jan Paul de Boer, Astrid E Greijer
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 18 Pg. 5061-70 (Sep 15 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22761471 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• Antibodies, Viral
• DNA, Viral
• Immunoglobulin G
• Deoxycytidine
• Valproic Acid
• Gemcitabine

Topics

• Antibodies, Viral (blood, immunology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Carcinoma
• Cell Line, Tumor
• DNA, Viral (genetics)
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Dose-Response Relationship, Drug
• Female
• Herpesvirus 4, Human (drug effects, immunology, pathogenicity)
• Humans
• Immunoglobulin G (blood, immunology)
• Male
• Middle Aged
• Nasopharyngeal Carcinoma
• Nasopharyngeal Neoplasms (drug therapy, pathology, virology)
• Neoplasm Staging
• Treatment Outcome
• Valproic Acid (administration & dosage)
• Viral Load
• Virus Activation (drug effects)
• Gemcitabine