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.

Bortezomib and SAHA Synergistically Induce ROS-Driven Caspase-Dependent Apoptosis of Nasopharyngeal Carcinoma and Block Replication of Epstein–Barr Virus

“…2A). To study the kinetics of apoptosis, HA and C666-1 cells were treated with 30 nmol/L bortezomib, 5 mmol/L SAHA, or their combination for different time duration (24,48, and 72 hours) and assayed for proteolytic cleavage of PARP and caspase-3 by Western blot analysis. Cleavage of PARP and caspase-3 was observed at an earlier time point upon treatment with both drugs (24 hours in HA cells and 48 hours in C666-1 cells) when compared with either drug alone (Fig.…”

“…Proteasome and HDAC inhibitors were also reported to induce EBV lytic cycle in different EBV-associated malignancies and lead to specific therapeutic effects against the cancer cells (11,12,23,24). Bortezomib was reported to induce EBV lytic cycle in EBV-positive Burkitt lymphoma and gastric carcinoma cells (25).…”

Regulation of the latent-lytic switch in Epstein–Barr virus

“…Recently, three patients with end-stage EBV-positive NPCs refractory to conventional therapy were treated with a combination of gemcitabine (a nucleoside analog used in chemotherapy), valproic acid, and ganciclovir [103]. Gemcitabine plus valproic acid had previously been shown to synergistically induce reactivation in EBV-positive NPC cells in vitro [96].…”

Therapeutic implications of Epstein–Barr virus infection for the treatment of nasopharyngeal carcinoma

“…All patients showed increased levels of viral DNA in the blood. Regarding clinical parameters, patients were in stable condition, developed only transient and moderate side effects, and experienced improvement in quality of life during and after treatment 224. Based on the results in this small population, a clinical trial with a larger sample size is currently underway in our center in collaboration with our Dutch colleagues.…”