Rationale, progress and development of vaccines utilizing STING-activating cyclic dinucleotide adjuvants

Abstract

A principal barrier to the development of effective vaccines is the availability of adjuvants and formulations that can elicit both effector and long-lived memory CD4 and CD8 T cells. Cellular immunity is the presumptive immune correlate of protection against intracellular pathogens: a group composed of bacteria, viruses and protozoans that is responsible for a staggering level of morbidity and mortality on a global scale. T-cell immunity is also correlated with clinical benefit in cancer, and the development of therapeutic strategies to harness the immune system to treat diverse malignancies is currently undergoing a renaissance. Cyclic dinucleotides (CDNs) are ubiquitous small molecule second messengers synthesized by bacteria that regulate diverse processes and are a relatively new class of adjuvants that have been shown to increase vaccine potency. CDNs activate innate immunity by directly binding the endoplasmic reticulum-resident receptor STING (stimulator of interferon genes), activating a signaling pathway that induces the expression of interferon-β (IFN-β) and also nuclear factor-κB (NF-κB) dependent inflammatory cytokines. The STING signaling pathway has emerged as a central Toll-like receptor (TLR) independent mediator of host innate defense in response to sensing cytosolic nucleic acids, either through direct binding of CDNs secreted by bacteria, or, as shown recently, through binding of a structurally distinct CDN produced by a host cell receptor in response to binding cytosolic double-stranded (ds)DNA. Although this relatively new class of adjuvants has to date only been evaluated in mice, newly available CDN-STING cocrystal structures will likely intensify efforts in this field towards further development and evaluation in human trials both in preventive vaccine and immunotherapy settings.

Nanoparticulate STING agonists are potent lymph node–targeted vaccine adjuvants

“…CDNs are a relatively new class of immunomodulatory compounds with the potential to promote protective immunity through a unique pathway using the cytosolic danger sensor STING and its downstream transcription factors NF-κB and IRF-3 (6,63). The publication of crystal structures demonstrating the structural basis for CDN sensing through STING (64,65) and the identification of endogenous CDNs as signaling products produced by cyclic GMP-AMP synthase sensing of double-stranded DNA (9,10,66) have provided both a rationale and mechanistic guidance for the development of CDNs as adjuvants acting through type I IFNs and NF-κB activation in host cells.…”

“…STING, which localizes to the endoplasmic reticulum, is a potent inducer of type I IFNs in response to sensing cyclic dinucleotides (CDNs) (6). The CDNs recognized by STING are small-molecule second messengers used by all phyla of bacteria (7) and are also produced as endogenous products of the cytosolic DNA sensor cyclic GMP-AMP synthase (8)(9)(10).…”

“…In parallel to these structural and molecular biology studies defining the pathways by which CDNs stimulate innate immunity, chemically synthesized CDNs, including cdGMP, cyclic di-inosine monophosphate, and cyclic di-AMP, are beginning to be explored as possible adjuvants for subunit vaccines, with particular success in promoting mucosal immunity to intranasal vaccines (6,(14)(15)(16). While these early studies point to the potential of CDNs as adjuvants promoting both T cell and humoral responses to subunit vaccines, the potency of STING agonists as parenteral adjuvants for systemic immunity remains unclear.…”

Induction of tumor regression by intratumoral STING agonists combined with anti–programmed death‐L1 blocking antibody in a preclinical squamous cell carcinoma model

“…16 CDNs formulated granulocyte-macrophage colony-stimulating factor producing vaccine (STINGVAX) upregulated programmed death-L1 and IFNg1CD81 T cells in the tumor microenvironment, and its combination with blocking programmed death-1 antibody induced regression of established tumors. 7,13,23 Work from others suggest that CDNs can also exert local and systemic antitumor effects as a monotherapy in several preclinical models. 11,13,16,22,23 Intraperitoneal injection with 5, 6-dimethylxanthenone-4-acetic acid, also a STING agonist, induces systemic antitumor activity in models of cervical, colon, and brain cancer.…”

Therapeutic cancer vaccines

“…In the case of short peptide vaccination in incomplete Freund's adjuvant (IFA), Therapeutic cancer vaccines must activate DCs with adjuvants. A crucial requirement of the proper action of SLP vaccines is the inclusion of appropriate adjuvants, including TLR ligands such as poly I:CLC (TLR3 ligand), CpG (TLR9 ligand) (50,(132)(133)(134)(135)146), Montanide (77-81, 83, 84, 132-135), or stimulator of IFN genes (STING) agonists (147). SLP vaccines can be further improved by the covalent coupling of a powerful TLR ligand to the peptide, leading to superior DC targeting and simultaneous DC activation (148)(149)(150).…”