Epstein-Barr virus-targeted therapy in nasopharyngeal carcinoma.
OBJECTIVE
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.


CONCLUSIONS
The treatment was safe with manageable side effects, clinical response was observed, and viral activation corroborated.
Department of Head and Neck Surgery and Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands, s.stoker@nki.nl.
Sharon D
SD
Stoker
Zlata
Z
Novalić
Maarten A
MA
Wildeman
Alwin D R
AD
Huitema
Sandra A W M
SA
Verkuijlen
Hedy
H
Juwana
Astrid E
AE
Greijer
I Bing
IB
Tan
Jaap M
JM
Middeldorp
Jan Paul
JP
de Boer
D000328:Adult; D000914:Antibodies, Viral / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002277:Carcinoma; D004279:DNA, Viral / Q000097:blood / Q000276:immunology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D004854:Herpesvirus 4, Human / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D013601:T-Lymphocytes / Q000187:drug effects; D014635:Valproic Acid / Q000008:administration & dosage; D017735:Virus Latency / Q000187:drug effects / Q000276:immunology; D000093542:Gemcitabine
D000914:Antibodies, Viral; D004279:DNA, Viral; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D003841:Deoxycytidine; D014635:Valproic Acid; D000093542:Gemcitabine