EBV-Related Lymphomas: New Approaches to Treatment

Jennifer A. Kanakry, Richard F. Ambinder

In the treatment of Epstein-Barr virus (EBV)-related lymphomas, there are few therapies specifically targeted against the latent virus within these tumors; in most cases the treatment approach is not different than the approach to EBV-negative lymphomas. Nonetheless, current and emerging therapies focused on exploiting aspects of EBV biology may offer more targeted strategies for EBV-positive lymphomas in the future. Conceptually, EBV-specific approaches include bolstering the antiviral/antitumor immune response with vaccines or EBV-specific cytotoxic T-lymphocytes, activating lytic viral genes to render the tumor cells susceptible to antiviral therapies, and inhibiting the downstream prosurvival or antiapoptotic pathways that may be activated by latent EBV proteins. EBV-specific cytotoxic T-cell infusions have proven effective in EBV-related posttransplantation lymphoproliferative disorder (EBV-PTLD) and expanding such adoptive immunotherapies to other EBV-related malignancies is an area of active research. However, other EBV-related lymphomas typically have more restricted, less immunogenic arrays of viral antigens to therapeutically target with adoptive immunotherapy compared with EBV-PTLD. Furthermore, the malignant EBV-positive tumor cells of Hodgkin lymphoma are scattered amid a dense infiltrate of regulatory T-cells, macrophages, and other cells that may dampen the antitumor efficacy of adoptive immunotherapy. Strategies to overcome these obstacles are areas of ongoing preclinical and clinical investigations. Some emerging approaches to EBV-related lymphomas include the coupling of agents that induce lytic viral replication with antiherpesvirus agents, or the use of small molecule inhibitors that block signaling pathways that are constitutively activated by EBV. EBV vaccines seem most promising for the treatment or prevention of EBV-related malignancies, rather than the prevention of primary EBV infection. EBV vaccine trials in patients with residual or low-bulk EBV-related malignancies or for the prevention of EBV-PTLD in EBV-seronegative patients awaiting solid organ transplantation are ongoing.