Cytolytic Virus Activation Therapy for Epstein-Barr Virus Driven Tumours
Menée sur des lignées cellulaires et 3 patients néerlandais atteints d'un carcinome du rhino-pharynx réfractaire aux traitements conventionnels, cette étude évalue les effets d'une stratégie thérapeutique à base de gemcitabine, d'acide valproïque et de valganciclovir pour le traitement de cancers liés au virus d'Epstein-Barr
Purpose: Nasopharyngeal carcinoma (NPC) is causally linked to Epstein-Barr virus (EBV). Since 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 few non-immunogenic proteins for EBV maintenance and contributing 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 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 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. Addition of GCV resulted in higher cytotoxicity compared to chemotherapy alone which was not observed in EBV negative cells. CLVA therapy was analyzed in 3 patients with end-stage NPC disease. Patients developed increased levels of viral DNA in the circulation originating from apoptotic tumor cells, had stabilized disease and experienced improved quality of life. Conclusions: Our results in the first 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.