Sodium valproate in combination with ganciclovir induces lysis of EBV‐infected lymphoma cells without impairing EBV‐specific T‐cell immunity

Abstract

Histone deacytelase inhibitiors (HDACi) represent a new class of anti-lymphoma therapeutics. Data in the clinical setting regarding on- and off-target effects of these agents are limited. Epstein-Barr virus (EBV)-positive lymphomas represent a highly defined system in which to make these observations. We present a case of a patient with multiple relapsed EBV-positive Diffuse Large B-cell Lymphoma that was chemo-refractory to anthracylcines, alkylating agents and rituximab. Treatment was commenced with the HDACi sodium valproate (VPA) in combination with the anti-viral nucleoside analogue ganciclovir (GCV). Therapy resulted in detectable cell-free unencapsulated circulating EBV-DNA providing supportive evidence for the first-time that lysis of virus infected lymphoma cells is induced using this therapeutic combination. EBV-specific CD8+ effector T-cell immunity was not impaired by VPA/GCV. Although GCV/VPA was insufficient to induce clinical remission, our data furthers the rationale that more potent HDAC inhibitors such as butyrate or gemcitabine together with GCV, perhaps in combination with chemotherapy, should be further investigated as therapy in relapsed/refractory EBV-positive lymphomas.

Association between Epstein-Barr Virus Infection and Chemoresistance to Docetaxel in Gastric Carcinoma

“…In one study, EBV-positive lymphoma was efficiently treated with ganciclovir (GCV) or azidothymidine (AZT) in vitro and in vivo following radiation-mediated lytic induction (Westphal et al, 2000). The EBV lytic cycle can be induced in EBV-infected cells by treatment with a variety of drugs, such as gemcitabine, doxorubicin, dexamethasone/rituximab, and valporic acid; subsequent treatment with GCV effectively induces apoptosis (Daibata et al, 2005;Feng et al, 2004;Jones et al, 2010). The therapeutic efficacy can be increased by controlling the Akt or MEKK1 signaling pathway in addition to treatment with the aforementioned drugs (He et al, 2008).…”

Cytolytic Virus Activation Therapy for Epstein-Barr Virus–Driven Tumors

“…This concept was first used in 1998 for the treatment of a patient with EBV-positive lymphoma in which a combination of an HDAC inhibitor with antiviral therapy was administered (12). This was followed by a study using valproic acid (VPA) instead of arginine butyrate (13). The combination of chemotherapy (5-FU) with an HDAC inhibitor (HDACi) for a stronger induction of the lytic cycle was evaluated in a Dutch patient with end-stage NPC.…”

Epstein-Barr Virus-Encoded miRNAs in Epstein-Barr Virus-Related Malignancy

“…For example, treatment of EBV-positive lymphoblastoid cells, or primary central nervous system lymphoma, with -irradiation promotes GCV-susceptibility of target cells. 15 Other studies successfully used 5-azacytidine, gemcitabine, doxorubicin, or a combination of anti-CD20 monoclonal antibody (Rituximab) and dexamethasone to induce lytic-phase gene expression and sensitize EBV-infected tumor cells to GCV or other nucleoside analogs. 15 Butyric acid, a short-chain fatty acid, and its derivatives have been experimentally employed in attempts to treat leukemias and other diseases.…”

“…15 Other studies successfully used 5-azacytidine, gemcitabine, doxorubicin, or a combination of anti-CD20 monoclonal antibody (Rituximab) and dexamethasone to induce lytic-phase gene expression and sensitize EBV-infected tumor cells to GCV or other nucleoside analogs. 15 Butyric acid, a short-chain fatty acid, and its derivatives have been experimentally employed in attempts to treat leukemias and other diseases. Butyrate induces the expression of certain EBV lytic proteins, including the thymidine kinase enzyme, from latent EBVinfected cells.…”

“…15 Various other agents have also been used to induce lytic replication of the EBV genome. For example, treatment of EBV-positive lymphoblastoid cells, or primary central nervous system lymphoma, with -irradiation promotes GCV-susceptibility of target cells.…”