Epstein-Barr virus-targeted therapy in nasopharyngeal carcinoma.

Abstract

PURPOSE:

Despite successful primary treatment of nasopharyngeal carcinoma (NPC), the incidence of distant metastasis remains 25-34 %. Treatment options are limited, and survival is poor. Intratumoural Epstein-Barr virus (EBV) was used as treatment target. In NPC, EBV is present in a latent state, expressing only few non-immunogenic viral products. Gemcitabine and valproic acid can trigger EBV to the lytic state, wherein viral kinases are expressed, making EBV-positive tumour cells susceptible for antiviral therapy with, i.e. valganciclovir, and inducing an EBV-specific immune response.

METHODS:

This drug combination was applied in eight patients with EBV-positive NPC, refractory to conventional treatment. The primary endpoints were safety, tolerability and clinical response. Secondary endpoint was to get proof of concept based on biomarkers, i.e. pharmacokinetics, EBV-DNA load in whole blood and nasopharyngeal brushes, EBV-RNA profiling for proof of lytic induction, EBV-IgG and EBV-IgA levels and diversity and EBV-specific T cell response.

RESULTS:

The best observed clinical response was partial in two patients (25 %) and stable disease in three patients (37.5 %). The median survival was 9 months (95 % confidence interval 7-17 months). Effective dose levels were reached. Peaking of EBV-DNA loads in blood and brush proved the biological effect on EBV during most treatment cycles. In one patient, RNA profiling confirmed lytic EBV induction. EBV-IgG and EBV-IgA antibody levels were already high before treatment and did not change during treatment. No changes in EBV-specific T cell response were detected.

CONCLUSION:

The treatment was safe with manageable side effects, clinical response was observed, and viral activation corroborated.

• Authors: Sharon D Stoker, Zlata Novalić, Maarten A Wildeman, Alwin D R Huitema, Sandra A W M Verkuijlen, Hedy Juwana, Astrid E Greijer, I Bing Tan, Jaap M Middeldorp, Jan Paul de Boer
• Journal: Journal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 141 Issue 10 Pg. 1845-57 (Oct 2015) ISSN: 1432-1335 [Electronic] Germany
• PMID: 25920375 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Adult
• Antibodies, Viral (immunology)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Carcinoma
• DNA, Viral (blood, immunology)
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Female
• Herpesvirus 4, Human (drug effects, immunology)
• Humans
• Immunoglobulin A (immunology)
• Immunoglobulin G (immunology)
• Male
• Middle Aged
• Nasopharyngeal Carcinoma
• Nasopharyngeal Neoplasms (blood, drug therapy, immunology, virology)
• T-Lymphocytes (drug effects)
• Valproic Acid (administration & dosage)
• Virus Latency (drug effects, immunology)
• Gemcitabine