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

TL;DR

This study shows that brincidofovir has strong anti-tumor effects in lymphoma models and may work well with immunotherapy.

Contribution

The study reveals brincidofovir's novel anti-tumor and immunogenic properties in lymphoma models.

Findings

Brincidofovir inhibited tumor growth in most cell lines at clinically relevant concentrations.

It triggered DNA damage and apoptosis while activating immune responses in lymphoma models.

Combining brincidofovir with anti-PD1 therapy enhanced tumor inhibition and immune activation.

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.

The online version contains supplementary material available at 10.1186/s12916-026-04680-8.

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