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Background <p>Brincidofovir (BCV) is a novel nucleoside phosphonate analogue with unique dual antiviral and anti-tumor properties.</p> Methods <p>The activity of BCV was evaluated in 44 cell-line models, including T/NK-cell non-Hodgkin lymphoma (T/NK-NHL, <i>n</i> = 25) and B-cell lymphoma (BCL, <i>n</i> = 19), and their respective NOD/SCID mice xenograft models. The potential immunogenic effects were examined in a syngeneic EL4-C57BL/6 murine lymphoma model.</p> Results <p>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).</p> Conclusions <p>Taken together, these results demonstrate a novel role for BCV in lymphoma therapy and suggest potential for combination with checkpoint immunotherapy.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月6日

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  • Jason Yongsheng Chan,
  • Elizabeth Chun Yong Lee,
  • Kelila Xin Ye Chai,
  • Boon Yee Lim,
  • Zhimei Li,
  • Jing Yi Lee,
  • Bavani Kannan,
  • Hui Yi Tay,
  • Tun Kiat Ko,
  • Jessica Sook-Ting Kok,
  • Kah Suan Lim,
  • Nur Ayuni Binte Muhammad Taib,
  • Dachuan Huang,
  • Jing Quan Lim,
  • Masatoshi Hazama,
  • Koji Fukushima,
  • Bin Tean Teh,
  • Soon Thye Lim,
  • Choon Kiat Ong

摘要

Background

Brincidofovir (BCV) is a novel nucleoside phosphonate analogue with unique dual antiviral and anti-tumor properties.

Methods

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.

Results

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).

Conclusions

Taken together, these results demonstrate a novel role for BCV in lymphoma therapy and suggest potential for combination with checkpoint immunotherapy.