Although important progress has been made in cytotoxic therapy for AIDS lymphomas, a substantial fraction of patients die with lymphoma or as a consequence of its therapy. New approaches which might augment or supersede conventional therapy are therefore needed. Healthy immunocompetent individuals and AIDS patients who are seropositive for Epstein Barr virus (EBV) demonstrate an intense cytotoxic memory T cell response to EBV latency antigens. However, the immunodominant viral latency antigens are not expressed in a variety of EBV-associated tumors including some EBV( +) diffuse large cell and immunoblastic lymphomas and all EBV( +) Ki-1, Burkitt's and Hodgkin's lymphomas. Restricted viral antigen expression in tumors and tumor cell lines correlates with methylation of transcriptional regulatory elements of the EBV genome. Treatment with 5-azacytidine in vitro at doses that are readily achievable in the clinic leads to demethylation of these regulatory elements, a promoter switch and expression of the full panel of EBV latency antigens including those most frequently targeted by cytotoxic T cells. A comparable effect on viral gene expression in tumors in vivo might facilitate immune destruction of these tumors. In this proposal we are seeking support for study of the molecular laboratory correlates of 5-azacytidine treatment of HIV patients with EBV lymphomas. The clinical trial will be conducted under the auspices of the Johns Hopkins Oncology Center Drug Development Program and will utilize the clinical resources of the General Clinical Research Inpatient Center. If effective in altering patterns of EBV gene expression, we hope to evaluate 5-azacitidine for therapeutic efficacy in the a cooperative group setting. Ultimately, this drug or its congeners might be used in place of conventional therapy or as """"""""consolidation"""""""" following conventional therapy to facilitate immune mediated destruction of residual tumor cells most resistant to conventional chemotherapy.
| Robertson, K D; Barletta, J; Samid, D et al. (1995) Pharmacologic activation of expression of immunodominant viral antigens: a new strategy for the treatment of Epstein-Barr-virus-associated malignancies. Curr Top Microbiol Immunol 194:145-54 |
| Siebert, J D; Ambinder, R F; Napoli, V M et al. (1995) Human immunodeficiency virus-associated Hodgkin's disease contains latent, not replicative, Epstein-Barr virus. Hum Pathol 26:1191-5 |
