Preclinical activity of brincidofovir in peripheral T-cell and NK/T-cell lymphoma.

Abstract

Brincidofovir (BCV) is a novel nucleoside phosphonate analogue with unique dual antiviral and anti-tumor properties. The activity of BCV was evaluated in 44 cell-line models, including T/NK-cell non-Hodgkin lymphoma (T/NK-NHL, n = 25) and B-cell lymphoma (BCL, n = 19), and their respective NOD/SCID mice xenograft models. The potential immunogenic effects were examined in a syngeneic EL4-C57BL/6 murine lymphoma model. BCV demonstrated potent anti-tumor activity across the majority of cell lines regardless of EBV positivity, with IC50 values within clinically achievable human plasma concentrations (2 µg/ml) in 17 of 25 (68.0%) T/NK-NHL and in 13 of 19 (68.4%) BCL. In vivo treatment significantly inhibited tumor growth in all xenograft models compared to vehicle control. Notably, RNAseq analysis demonstrated BCV downregulated MYC-target pathways in T/NK-NHL models. BCV evoked S-phase cell cycle arrest, replication stress, DNA damage, and apoptosis while triggering STING pathway-mediated interferon responses, PD-L1 expression, and immunogenic cell death. In the EL4-C57BL/6 model, BCV in combination with anti-PD1 significantly inhibited tumor growth and triggered an immune reaction characterized by the highest scores for adaptive immune response, cytokines/chemokines and receptors, cytotoxic cells, dendritic cells, NK CD56dim cells, and neutrophils (NanoString Immunology Panel). Taken together, these results demonstrate a novel role for BCV in lymphoma therapy and suggest potential for combination with checkpoint immunotherapy.