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Preclinical activity of brincidofovir in Peripheral T-cell and NK/T-cell Lymphoma

ABSTRACT: Introduction: Brincidofovir (BCV) is a novel nucleoside phosphonate analogue with unique dual anti-viral and anti-tumor properties. Results: BCV demonstrated potent anti-tumor activity in vitro across the majority of cell-lines regardless of EBV positivity, with IC50 values within clinically-achievable human plasma concentrations (2 µg/ml) in 17/25 (68.0%) T/NK-NHL and in 13/19 (68.4%) BCL. In vivo treatment via intraperitoneal BCV (IP, 40mg/kg, 2X per week) significantly inhibited tumor growth in all xenograft models when compared to vehicle control. Notably, RNAseq analysis demonstrated BCV downregulated MYC and MYC-target pathways in T/NK-NHL models. Further mechanistic studies showed that BCV evoked S-phase cell cycle arrest, replication stress, DNA damage and apoptosis, while also triggering STING pathway-mediated interferon responses, PD-L1 expression and immunogenic cell death. In the syngeneic EL4-C57BL/6 model, BCV in combination with anti-PD1 significantly inhibited tumor growth and triggered an immune reaction characterized by highest scores for adaptive immune response, cytokines/chemokines & receptors, cytotoxic cells, dendritic cells, NK CD56dim cells and neutrophils (NanoString Immunology Panel). Conclusions: Taken together, these results demonstrate a novel role of BCV in the treatment of lymphoma, and suggest potential for combination with checkpoint immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE293367 | GEO | 2026/03/18

REPOSITORIES: GEO

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Project description:Natural Killer (NK) cells are phenotypically and functionally diverse lymphocytes that recognize and kill cancer cells. The susceptibility of target cancer cells to NK cell-mediated cytotoxicity depends on the strength and balance of regulatory (activating/inhibitory) ligands expressed on target cell surface. We performed gene expression arrays to determine patterns of NK cell ligands associated with B-cell non-Hodgkin lymphoma (b-NHL). Microarray analyses revealed differential upregulation of a multitude of NK-activating and costimulatory ligands across varied lymphoma cell lines and b-NHL cells including ULBP1, CD72, CD48 and SLAMF6. To correlate genetic signatures with functional anti-lymphoma activity, we developed a dynamic and quantitative cytotoxicity assay in an integrated microfluidic droplet array. This assay facilitated the examination of transient interactions between NK cells and target lymphoma cells and also the functional heterogeneity in NK cell effector outcomes at single-cell level. Individual NK cells and target lymphoma cells were co-encapsulated in picoliter-volume droplets and imaged over time to quantify heterotypic cell-cell interaction. We identified significant variability in NK-lymphoma cell contact duration, frequency and subsequent cytolysis. The death of lymphoma cells undergoing single contact with NK cells occurred faster than cells that made multiple short contacts. NK cells also killed target cells in droplets via contact-independent mechanisms that partially relied on calcium-dependent processes and perforin secretion, but not on cytokines (IFN-γ or TNF-α). We extended this technique to characterize cytolysis of primary cells from b-NHL patients. Diffuse large B-cell lymphoma cells from two patients showed similar contact durations with NK cells; primary Burkitt lymphoma cells made longer contacts and were lysed at later times. We further tested the cytotoxic efficacy of NK-92, a continuously growing NK cell line being investigated as an anti-tumor therapy, using our droplet-based bioassay. NK-92 cells were found to be more efficient in killing b-NHL cells compared with primary/fresh NK cells, requiring shorter contacts for faster killing activity. Taken together, our combined genetic and microfluidic analysis demonstrate significant heterogeneity in the dynamic interaction and associated cytotoxicity between NK cellular therapy and b-NHL cells.

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Preclinical activity of brincidofovir in Peripheral T-cell and NK/T-cell Lymphoma

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