Treatment of Epstein-Barr virus-associated malignancies with specific T cells

Latent Epstein-Barr virus (EBV) infection is associated with a heterogeneous group of malignancies, including Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma, and lymphoproliferative disease (LPD). The development of adoptive immunotherapies for these malignancies is being fueled by the successful generation of allogeneic donor derived EBV-specific cytotoxic T cells (CTL) for the prevention and treatment of EBV-LPD after hematopoietic stem cell transplantation. This approach is being extended to EBV-LPD after solid organ transplantation by use of autologous and haploidentical EBV-specific CTL. For other EBV-associated malignancies, there is only limited clinical experience with EBV-specific CTL. With few exceptions, only patients with recurrent Hodgkin's disease have been treated with autologous EBV-specific CTL, and although the results have been promising, they do not include cures. Lack of CTL efficacy may reflect either down-regulation of immunodominant EBV proteins, which are major CTL targets, or the presence of inhibitory cytokines. Further improvement of EBV-specific CTL therapy for Hodgkin's disease will require improved methods to activate and expand CTL specific for the latent EBV genes expressed in Hodgkin's disease and to genetically modify the expanded CTL to render them resistant to inhibitory cytokines. If effective, such strategies could be applied not only to other EBV-associated malignancies, but also to a broad range of human tumors with defined tumor antigens and similar immune evasion strategies.