Pedersen, M.; Hubbard, L. C.; Foo, S.; Patrikeev, A.; Rullan, A.; Baldock, H.; Mandl, C.; Chetta, P.; Hassan, J.; Dean, I. W.; Guppy, N.; Slos, P.; Chan Wah Hak, C.; Appleton, E.; Patin, E. C.; Weir, J.; Ono, M.; Oost, T.; Reiser, U.; Zichner, T.; Morse, K.; Murphy, M.; Luo, L.; House, R.; Giffin, L.; Melcher, A.; Vogt, A.; Carotta, S.; Harrington, K. J.

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), which was designed for intravenous delivery, was investigated for anti-tumour and immunological effects. 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 synergizes to generate innate immune cell and CD8+ T cell responses that control tumour growth. Anti-tumour activity induced by combined RT / STINGa was reduced in mice lacking a functional immune system. RT / STINGa combination treatment also initiated development of protective immune memory. 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. Our data confirm STING as a therapeutic target in cancer and support the clinical development of BI-1703880 STING agonist, thereby suggesting radiotherapy as a potential combination for enhancing anti-tumour efficacy.