STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade

Abstract

Stimulator of interferon genes (STING) is a cytosolic receptor that senses both exogenous and endogenous cytosolic cyclic dinucleotides (CDNs), activating TBK1/IRF3 (interferon regulatory factor 3), NF-κB (nuclear factor κB), and STAT6 (signal transducer and activator of transcription 6) signaling pathways to induce robust type I interferon and proinflammatory cytokine responses. CDN ligands were formulated with granulocyte-macrophage colony-stimulating factor (GM-CSF)–producing cellular cancer vaccines—termed STINGVAX—that demonstrated potent in vivo antitumor efficacy in multiple therapeutic models of established cancer. We found that rationally designed synthetic CDN derivative molecules, including one with an Rp,Rp dithio diastereomer and noncanonical c[A(2′,5′)pA(3′,5′)p] phosphate bridge structure, enhanced antitumor efficacy of STINGVAX in multiple aggressive therapeutic models of established cancer in mice. Antitumor activity was STING-dependent and correlated with increased activation of dendritic cells and tumor antigen–specific CD8+ T cells. Tumors from STINGVAX-treated mice demonstrated marked PD-L1 (programmed death ligand 1) up-regulation, which was associated with tumor-infiltrating CD8+IFNγ+ T cells. When combined with PD-1 (programmed death 1) blockade, STINGVAX induced regression of palpable, poorly immunogenic tumors that did not respond to PD-1 blockade alone.

The head and neck cancer immune landscape and its immunotherapeutic implications

“…We therefore hypothesize that smoking signature-high HNSCC may benefit from immune modulators such as IL-2, TLR, and STING agonists used in other cancer types to boost overall host immunity. This may facilitate the response to checkpoint blockade, similar to results in other recent studies (76). It is possible that checkpoint blockade alone could potentially drive increased immune infiltration in smoking signature-high tumors in a chemokine-dependent fashion.…”

The host STING pathway at the interface of cancer and immunity

“…The 2′,3′ mixed linkage structure confers increased STING binding affinity (52) and is also found in endogenous cGAMP produced by eukaryotic cGAS. ML RR-S2 CDA was shown to broadly activate all known human STING alleles in a HEK293T cellular STING signaling assay and induced dose-dependent expression of IFN-β in human peripheral blood monocytes (PBMCs) isolated from multiple donors with different STING genotypes, including a donor homozygous for the REF allele, which is known to be refractory to signaling induced by bacterial 3′,3′ CDNs (8,86). ML RR-S2 CDA was evaluated in multiple syngeneic mouse tumor models, including B16.F10 melanoma, 4T1 mammary carcinoma, and CT26 colon carcinoma, and demonstrated a potent antitumor immune response and significant tumor regression in each model (8).…”

“…It became possible to test the effects of STING activation when it was discovered that the cells, and induced more potent antitumor immunity compared with CDNs that did not contain a dithio modification (8,86). To increase affinity for human STING, ML RR-S2 CDA contains a noncanonical structure defined by a phosphate bridge with one 2′-5′ and one 3′-5′ mixed phosphodiester linkages (2′,3′ CDNs).…”

Heating it up: Oncolytic viruses make tumors ‘hot’ and suitable for checkpoint blockade immunotherapies

“…Of note, other mechanistically similar strategies using adjuvant-like immunostimulators (such as STING pathway agonists) have been reported to sensitize tumors to subsequent immune checkpoint blockade, further strengthening the argument for such a combinatorial approach. 14 , 15 Similarly, it has been shown that immunogenic cell death (ICD) inducers such as oxaliplatin and cyclophosphamide sensitize KRAS-induced lung cancers to subsequent immune checkpoint blockade. 16 It is not unreasonable to postulate that viruses, in particular T-VEC, can induce ICD because T-VEC has been genetically modified to remove genes that suppress the immune response and accentuate the premortem stress responses, including the type-1 interferon response, that characterize ICD.…”