Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy

Abstract

Immune checkpoint inhibitors (ICI) have revolutionised cancer therapy. However, they have been effective in only a small subset of patients and a principal mechanism underlying immune-refractoriness is a ‘cold’ tumour microenvironment, that is, lack of a T-cell-rich, spontaneously inflamed phenotype. As such, there is a demand to develop strategies to transform the tumour milieu of non-responsive patients to one supporting T-cell-based inflammation. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway is a fundamental regulator of innate immune sensing of cancer, with potential to enhance tumour rejection through the induction of a pro-inflammatory response dominated by Type I interferons. Recognition of these positive immune-modulatory properties has rapidly elevated the STING pathway as a putative target for immunotherapy, leading to a myriad of preclinical and clinical studies assessing natural and synthetic cyclic dinucleotides and non-nucleotidyl STING agonists. Despite pre-clinical evidence of efficacy, clinical translation has resulted into disappointingly modest efficacy. Poor pharmacokinetic and physiochemical properties of cyclic dinucleotides are key barriers to the development of STING agonists, most of which require intra-tumoral dosing. Development of systemically administered non-nucleotidyl STING agonists, or conjugation with liposomes, polymers and hydrogels may overcome pharmacokinetic limitations and improve drug delivery. In this review, we summarise the body of evidence supporting a synergistic role of STING agonists with currently approved ICI therapies and discuss whether, despite the numerous obstacles encountered to date, the clinical development of STING agonist as novel anti-cancer therapeutics may still hold the promise of broadening the reach of cancer immunotherapy.

Intratumoral immunotherapy with STING agonist, ADU-S100, induces CD8+ T-Cell mediated anti-tumor immunity in an esophageal adenocarcinoma model

“…In this study we evaluate the impact of a STING agonist, ADU-S100, a synthetic cyclic dinucleotide (CDN) agonist of STING, known to activate all human and mouse STINGs and induce the expression of cytokines and chemokines [ 18 ], in combination with radiation, on local tumor control and effector T-cell functionality using the modified Levrat model for esophageal adenocarcinoma (EAC). This surgical model of end-to-side esophagojejunostomy in rats causes chronic gastroduodenoesophageal reflux disease (GDER) inducing the development of de novo EAC through identical physiological and molecular processes that occur in humans [ 19 , 20 ].…”

Intratumoral STING Agonist Injection Combined with Irreversible Electroporation Delays Tumor Growth in a Model of Hepatocarcinoma

“…However, these molecules are susceptible to enzymatic degradation, having low bioavailability in target tissues and producing unwanted toxicities. New drug delivery systems are being explored to address these challenges [ 23 ].…”

Effective delivery of STING agonist using exosomes suppresses tumor growth and enhances antitumor immunity

“…Cytosolic DNA is converted to cyclic GMP-AMP (cGAMP) by cGAS (cyclic GMP-AMP synthase). The STING protein on the endoplasmic reticulum of DCs responds to cGAMP by activating the transcription of type I interferon and cytokines, which in turn activates and primes antigen-specific CD8 + T cells ( 6 , 7 ). In the context of tumors, STING activation can also influence the immune microenvironment by limiting the accumulation of MDSCs and Tregs and by promoting M1-macrophage polarization ( 4 ).…”

“…The utility of STING agonist (STINGa), namely cGAMP and other cyclic dinucleotides (CDNs), in the treatment of cancer is in early phase of clinical testing ( 7 ), and ongoing efforts are directed toward overcoming its unfavorable pharmacological profile and poor bioavailability ( 9 , 10 , 11 , 12 ). Despite extensive preclinical studies indicating antitumor efficacy of STINGa, notably in synergy with other immune modulators, initial efforts in the development of pharmacological STINGa resulted in marginal benefit in patients, prompting the development of agonists with enhanced stability ( 13 ).…”