Perera et al. synthesized MSA-1, a novel cross-reactive mouse and human STING agonist with greater in vitro potency than the natural ligand cGAMP, and evaluated it in a panel of syngeneic and immune-deficient mouse tumor models. Intratumoral (IT) MSA-1 administration resulted in dose-dependent tumor growth inhibition in injected and non-injected tumors, which was STING-dependent and due in part to induced TNFα activity and direct systemic MSA-1 exposure. IT MSA-1 enhanced the activity of PD-1 inhibitors in anti-PD-1-resistant models, and stimulated genes affected by PD-1 inhibition, but more rapidly and strongly.
Contributed by Katherine Turner
ABSTRACT: The innate immune agonist STING (STimulator of INterferon Genes) binds its natural ligand 2'3'-cGAMP (cyclic guanosine-adenosine monophosphate) and initiates type I interferon production. This promotes systemic antigen-specific CD8+ T-cell priming that eventually provides potent anti-tumor activity. To exploit this mechanism, we synthesized a novel STING agonist, MSA-1, that activates both mouse and human STING with higher in vitro potency than cGAMP. Following intratumoral (IT) administration of MSA-1 to a panel of syngeneic mouse tumors on immune-competent mice, cytokine upregulation and its exposure were detected in plasma, other tissues, injected tumors, and noninjected tumors. This was accompanied by effective anti-tumor activity. Mechanistic studies in immune-deficient mice suggested that anti-tumor activity of IT-dosed STING agonists is in part due to necrosis and/or innate immune responses such as tumor necrosis factor _ (TNF-_) activity, but development of a robust adaptive anti-tumor immunity is necessary for complete tumor elimination. Combination with PD-1 blockade in anti-PD-1-resistant murine models demonstrated that MSA-1 may synergize with checkpoint inhibitors but can also provide superior tumor control as a single agent. We show for the first time that potent cyclic dinucleotides can promote a rapid and stronger induction of the same genes eventually regulated by PD-1 blockade. This may have contributed to the relatively early tumor control observed with MSA-1. Taken together, these data strongly support the development of STING agonists as therapy for patients with aggressive tumors that are partially responsive or nonresponsive to single-agent anti-PD-1 treatment by enhancing the anti-PD-1 immune profile.