Apoptotic modulators enhance oncolytic virus-induced cytokine killing in acute myeloid leukaemia (AML)
Menée à l'aide de lignées cellulaires d'origine humaine ainsi que d'échantillons de cellules mononucléaires (PBMC) provenant de personnes saines ou de patients atteints d'une leucémie myéloïde aiguë, cette étude met en évidence l'intérêt des modulateurs de l'apoptose (mimétiques de BH3 et SMAC) pour renforcer l'effet cytotoxique de cytokines dont la sécrétion a été induite par un virus oncolytique
Background : Approximately 3000 adult patients are diagnosed with AML in the UK each year. Current intensive treatments are not well-tolerated by elderly patients, and the 5-year survival rate is only 5–15%, highlighting the need for novel and effective therapies. Oncolytic viruses (OVs) preferentially replicate in cancer cells, resulting in direct oncolysis and induction of innate and adaptive anti-tumour immunity. Unfortunately, the efficacy of OVs remains relatively unexplored in AML.
Methods : Using human AML cell lines, healthy-donor peripheral blood mononuclear cells (PBMC) and AML patient samples, we investigated whether combination with clinically applicable apoptotic modulators (SMAC/BH3 mimetics) can potentiate OV-induced cytokine-mediated killing.
Results : We confirmed that OVs stimulate PBMCs to produce inflammatory cytokines, which can induce AML cell death. Bystander cytokine-mediated killing was also significantly enhanced in combination with SMAC/BH3 mimetics, with the optimal combination partner varying with AML subtype. We identified interferon (IFN)-
α and tumour necrosis factor (TNF)-α as potential mediators of AML cytotoxicity, and SMAC/BH3 mimetics enhanced AML cell death following direct OV infection, indicating autocrine-paracrine signalling events. Pivotally, we confirmed that apoptotic modulators were effective in combination with both Live- and UV-inactivated virus.
Conclusion
:
This work has identified a novel reovirus-based combination-immunotherapy for the treatment of AML.
British Journal of Cancer , article en libre accès, 2026