From pathobiology to targeted treatment in Epstein Barr virus related T cell and Natural Killer cell lymphoproliferative diseases

Epstein Barr virus (EBV), a gamma-1 herpesvirus, establishes a life-long latent infection in the majority of individuals worldwide. Whilst this seemingly innocuous virus is carried as an asymptomatic infection of memory B cells, EBV is paradoxically linked to two pre-malignant lymphoproliferative diseases (LPDs) and up to nine aetiologically distinct human tumours, accounting for up to 200,000 cancers per year. Although these malignancies primarily occur in B cells and epithelial cells, correlating with the natural tropism of the virus, on rare occasions EBV also infects T and NK cells leading to various pre-malignant LPDs, lymphomas and leukaemia. These conditions are often highly aggressive and are associated with hyperinflammation and organ dysfunction leading to substantial mortality. While, in recent years improvements in chemotherapy, especially asparaginase based regimens, have led to improved outcomes for some, these conditions are often intrinsically chemoresistant with allograft often providing the only curative option. In this review, we address the impact of genetic and epigenetic changes on the pathogenesis of the T/NK cell LPDs and bring together an analysis of recent clinical trials attempting to target these processes. We describe the main molecular characteristics across the range of EBV-associated T/NK cell diseases, from somatic mutations effecting epigenetic regulators seen across EBV related T/NK LPD subtypes to the marked dysregulation of the JAK-STAT-MYC axis observed in higher grade disease such as extranodal NK/T lymphoma (ENKTL). We then go on to analyse the novel therapeutic options available including immunomodulation and small molecule inhibitors. While these approaches show promise in early phase trials there is still much scope for improvement and a need to better understand the pathophysiology to design rational combination treatments.