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

BACKGROUND: As 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. METHODS: We 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. RESULTS: We 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. CONCLUSIONS: Our 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.