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