arginine-butyrate and Lymphoproliferative-Disorders

Epstein-Barr virus-associated posttransplant lymphoproliferative disease (PTLD) is a life-threatening complication of organ transplantation. As we continue to observe improved outcomes of patients living after solid or hematopoietic stem cell transplantation, we can expect to see a parallel increase in the incidence of PTLD. Several innovative therapeutic approaches are currently under development to add to our arsenal of treatment strategies in this devastating disease.. The past decade has witnessed significant progress in the understanding and treatment of PTLD. The tolerability and effectiveness of standard treatment regimens, such as a reduction in immunosuppression, rituximab, and chemotherapy, have been confirmed and improved upon. Newer options for treatment demonstrating significant promise include antiviral therapy with arginine butyrate, as well as Epstein-Barr virus-specific cytotoxic T-cell therapy.. Both the heterogeneous PTLD population and the lack of standardized and evidence-based treatment approaches make treatment a difficult decision for the clinician. This article reviews and updates the evidence behind accepted strategies such as reduction in immunosuppression, rituximab, and chemotherapy, as well as explores novel and effective therapeutic modalities including antiviral therapy with arginine butyrate and adoptive allogeneic T-cell therapy.

Topics: Adoptive Transfer; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Arginine; Butyrates; Epstein-Barr Virus Infections; Hematopoietic Stem Cell Transplantation; Herpesvirus 4, Human; Humans; Immunologic Factors; Lymphoproliferative Disorders; Rituximab; T-Lymphocytes, Cytotoxic

Lymphoproliferative disorders associated with the Epstein-Barr virus (EBV) include non-Hodgkin's lymphoma, Hodgkin's lymphoma, and "post-transplant lymphoproliferative disorders" (PTLD), which occur with immunosuppression after marrow and organ transplantation. PTLD is characterized by actively proliferating, latently infected EBV(+) B-lymphocytes, and often manifests a rapidly progressive fatal clinical course if the immunosuppression cannot be reversed. Lung transplant recipients are a subset of patients at special risk for developing PTLD. The incidence of PTLD development in these patients has been estimated at 5--10%. Whereas immunologic and antiviral therapy have been moderately effective for treating EBV-associated infections in the lytic phase, they have been less useful in the more common latent phase of the disease. One common treatment for herpesvirus infections has targeted the virus-specific enzyme thymidine kinase (TK). The lack of viral TK expression in EBV(+) tumor cells, due to viral latency, makes anti-viral therapy alone ineffective as an anti-neoplastic therapy, however. We have developed a strategy for the treatment of EBV-associated lymphomas/PTLD using pharmacologic induction of the latent viral TK gene and enzyme in the tumor cells, followed by treatment with ganciclovir. Arginine butyrate selectively activates the EBV TK gene in latently EBV-infected human lymphoid cells and tumor cells. A Phase I/II trial has been initiated, employing an intra-patient dose escalation of arginine butyrate combined with ganciclovir. In six patients with EBV-associated lymphomas or PTLD, all of which were resistant to conventional radiation and/or chemotherapy, this combination produced complete clinical responses in four of six patients, with a partial response occurring in a fifth patient. Pathologic examination in two of three patients demonstrated complete necrosis of the EBV lymphoma, with no residual disease, following a single three-week course of the combination therapy. Possible side-effects of the therapy included nausea and reversible lethargy at the highest doses. One patient suffered acute liver failure, thought to be secondary to release of FasL from the necrotic tumor. Analysis of patient-derived tumor cells in culture demonstrated that arginine butyrate produced selective induction of the EBV TK gene, which then conferred sensitivity to ganciclovir, resulting in tumor apoptosis. Additional patient accrual is sought for further evalua

Topics: Antineoplastic Agents; Antiviral Agents; Arginine; Butyrates; Drug Therapy, Combination; Epstein-Barr Virus Infections; Ganciclovir; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Viral; Herpesvirus 4, Human; Humans; Lung Neoplasms; Lung Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Tumor Cells, Cultured; Virus Latency