CD20 Bispecific T cell Engager Depletes B Cell Progenitors Preventing EBV-Associated Lymphomagenesis in Humanized...

Epstein Barr virus (EBV) infection is associated with around 1.5% of human tumors, including B cell lymphoproliferative diseases (LPD). A common approach in treating EBV-associated LPDs is targeting infected tumor cells with a CD20 monoclonal antibody, such as Rituximab, although this often fails to prevent relapse and refractory disease. In this study, we show in a pre-clinical humanized mouse model superior efficacy of a CD3xCD20 bispecific T cell engager (CD20 TCE) in preventing systemic virus spread and EBV-associated tumor formation as compared to Rituximab treatment. Increased efficacy is associated with a deep depletion of human precursor B cells in the bone marrow. Progenitor B cells are permissive to infection with EBV in vitro and correlate with EBV persistence during B cell depletion therapy also in vivo. Thus, deep depletion of B cells including bone marrow progenitors might target EBV-associated LPDs more efficiently and infected progenitors should be considered as an EBV reservoir from which associated pathologies could relapse.