Short-Term Exposure to Arginine Butyrate, in Combination with Ganciclovir, Is as Effective as Continuous Exposure for Virus-Targeted Therapy of EBV-Positive Lymphomas.

Abstract 4754

Antiviral drugs alone have been unsuccessful in the treatment of Epstein-Barr virus (EBV)-associated malignancies because the virus maintains a latent state of replication in these tumors. In recent years, we developed a novel therapeutic approach wherein the early lytic phase of the virus is induced prior to the use of cytotoxic antiviral drugs. Butyrate derivatives induce an early lytic pattern of EBV gene expression in patient-derived EBV-positive lymphoblastoid cell lines and, together with the nucleoside analog ganciclovir (GCV), effectively reduce or eliminate tumor growth in humans. In a completed Phase 1/2 trial in which patients with relapsed or refractory EBV-associated lymphoid malignancies were treated with 3 weeks of Arginine Butyrate combined with GCV, tumor responses (CR and PR) occurred in 10 of 15 patients. Butyrate requires administration by prolonged intravenous infusion, which is challenging over long time periods. In the Phase 1/2 clinical trial, tumor responses were observed within a few days of starting therapy. We therefore investigated whether brief or discontinuous exposure to Butyrate is also capable of initiating early lytic-phase gene expression and thymidine kinase induction, and sensitizing EBV-positive lymphoma cells to ganciclovir-mediated cell growth arrest and apoptosis. Multiple daily 6-hr exposures of the EBV-positive Burkitt's lymphoma cell line P3HR1 to butyrate induced sustained expression of the EBV TK and lytic-phase protein BMRF. Discontinuous exposure to butyrate in combination with ganciclovir also induced a similar level of tumor cell death as did continuous treatment, as measured by serial enumeration of viable cells, MTT cell proliferation assays, and measurement of cellular DNA content. Based on these observations, we have initiated a new clinical trial utilizing a 5-day infusion of Arginine Butyrate and 21 days of GCV/valganciclovir for treatment of patients with EBV-positive lymphoid malignancies. The first patient enrolled, with Rituximab-refractory EBV-positive PTLD following a cord stem cell transplant for Hodgkin's Disease, has been treated on this protocol. The therapy was well-tolerated and resulted in rapid resolution of fever and cough of several weeks duration, and a rapid decrease of markedly elevated LDH levels to the normal range. At the end of the first cycle, 4 of 6 target lesions resolved completely, and two additional lesions decreased in size. High EBV, CMV and HHV6 viral loads became undetectable. This response has been durable for 2 months. These findings together suggest that a shorter, more patient-accessible regimen of this virus-targeted therapeutic strategy may be efficacious, and the clinical trial is continuing.