Synthetic Cyclic Dinucleotides Are Potent Cancer Vaccine Adjuvants

Stimulator of interferon genes (STING, also known as TMEM173) is a cytosolic receptor that elicits type I IFN and proinflammatory cytokine signaling when activated by exogenous or endogenous cyclic dinucleotides (CDN). STING functions as a central regulator of innate immune responses, which have been shown to modulate the activity of cancer vaccines, prompting Fu and colleagues to develop STINGVAX, a granulocyte-macrophage colony-stimulating factor (GM-CSF)–secreting whole-cell vaccine formulated with CDNs. In comparison with an unformulated GM-CSF–secreting vaccine, STINGVAX generated an increased antitumor response in multiple tumor models. Mechanistically, STINGVAX indirectly induced STING-dependent tumor cell killing via increased activation of dendritic cells (DC) and CD8⁺ tumor-infiltrating lymphocytes (TIL). To increase the stability and binding of CDN to polymorphisms of human STING, the authors rationally designed synthetic CDN derivatives with more potent immunostimulatory capacity. In comparison with canonical CDNs, synthetic phosphodiesterase-resistant CDNs with a dithio diastereomer and noncanonical phosphate bridge linkage demonstrated more potent activation of human antigen-presenting cells. Moreover, these synthetic CDN derivatives enhanced the production of IFNα and IL12 in human DCs and potently stimulated a T_H1 response, regardless of the human STING genotype, resulting in increased antitumor efficacy in tumor models. Importantly, STINGVAX treatment upregulated the expression of programmed death ligand 1 (PD-L1), indicative of adaptive immune resistance, which correlated with increased infiltration of CD8⁺IFNγ⁺ TILs. Combined treatment with PD-1–blocking antibody and synthetic CDN–formulated STINGVAX resulted in improved antitumor responses and regression of established tumors that were resistant to PD-1 blockade alone. In sum, these findings demonstrate that STINGVAX provides therapeutic immunity against cancer in preclinical models and support clinical trials to evaluate STINGVAX in combination with PD-1 blockade or other immune checkpoint inhibition.

Fu J, Kanne DB, Leong M, Glickman LH, McWhirter SM, Lemmens E, et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci Transl Med 2015;7:283ra52.

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