British journal of cancer · 2026
Apoptotic modulators enhance oncolytic virus-induced cytokine killing in acute myeloid leukaemia (AML).
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Askar Basem, Heaton Samuel, Barr Tyler, Baugh Richard, Alzamel Noura, McConnell Stewart, Jennings Victoria A, Volpato Milene, Ralph Christy, Jain Manish, Kelly Richard J, Parrish Christopher, Errington-Mais Fiona
Аннотация
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.
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.