Preclinical efficacy of a systemically-administered, second-generation STING agonist that promotes anti-tumour immunity in combination with radiotherapy.

backgroundAs potent triggers of innate immunity, STING agonists hold promise as active immunotherapeutic agents for cancer treatment. Second-generation STING agonists, suitable for systemic delivery, are being investigated in preclinical research and have entered clinical trials. Here, the novel synthetic STING agonist, BI-1703880 (STINGa), was investigated for anti-tumour and immunological effects.

methodsWe used human and murine immune and tumour cells to examine the effects of STINGa in vitro, and preclinical cancer mouse models to investigate effects in vivo.

resultsWe show that STINGa activates the STING pathway and results in a transient and dose-dependent upregulation and secretion of interferons and proinflammatory cytokines in vitro and in vivo. We show that intravenous administration of repeated dosing with low-dose STINGa is well tolerated. We report that radiotherapy (RT) and STING agonism synergises to generate innate immune cell and CD8+ T cell responses that control tumour growth. RT/STINGa upregulated PD-L1, PD-1 and CTLA-4 in the tumour microenvironment. Our findings show that combining RT/STINGa with immune checkpoint inhibitors further increases therapeutic benefit.

conclusionsOur data confirm STING as a therapeutic target in cancer and support the clinical development of BI1703880 STING agonist, thereby suggesting radiotherapy as a potential combination for enhancing anti-tumour efficacy.