Epstein-Barr Virus is a common and worldwide pathogen. While exposure usually results in a self-limited lymphoproliferative syndrome, infectious mononucleosis, the virus is causative, or associated with, a number of malignancies. The latent virus is detected in 2 endemic tumors: 95% of African Burkitt's lymphoma, and 90-100% of nasopharyngeal carcinoma. Many B-lymphomas, some T-lymphomas, and approximately 50% of Hodgkin's lymphomas have also been found to contain latent EBV. 40% of lymphomas arising in AIDS, and nearly all lymphomas arising in transplant recipients (post-transplant-associated lymphoproliferative disease (PT-LPD) harbor EBV. PT-LPD is especially difficult to treat unless the immunosuppression can be reversed, and is typically refractory to radiation therapy and chemotherapy. Similar to herpes simplex virus and varicella-zoster virus, EBV encodes a thymidine kinase (TK) enzyme. In a rate-limiting step, the viral TK converts nucleoside analogues to their monophosphate form, eventually leading to premature termination of the nascent DNA and cell death. Latently-EBV-infected B-cells and epithelial cells, including tumor cells, do not express TK. We have found that exposure of these cells to the experimental drug Arginine Butyrate results in induction of TK expression. Preliminary in vitro studies demonstrated that induction of EBV-TK in patient-derived tumor cells by Arginine Butyrate is possible, and that these previously-resistant cells are rendered susceptible to Ganciclovir (GCV) therapy. We have years of clinical experience in the administration of Arginine Butyrate to adults and children in studies to induce fetal hemoglobin as therapy for sickle cell anemia and thalassemia. We hypothesized that treatment of patients with EBV- associated tumors with arginine butyrate (to induce the EBV-TK) and GCV (to eliminate EBV-TK expressing cells) might be an effective, nontoxic therapy. We have treated eight patients with Arginine Butyrate plus ganciclovir in an FDA-registered pilot study with documented responses in the majority of patients, and no adverse outcomes related to this regimen.
Our Specific Aims are: (1) To determine if treatment with Arginine Butyrate plus Ganciclovir will result in clinical responses in a significant proportion of patients with EBV-associated lymphomas and lymphoproliferative disease (LPD); (2) To determine toxicity or side effects of the combination therapy; and (3) To determine if tumor specimens and cell lines derived from patients demonstrate the same response to Arginine Butyrate and Ganciclovir (with respect to TK gene induction and synergistic susceptibility) as the EBV(+) cell lines we have studied to date.
