The Age of Cyclic Dinucleotide Vaccine Adjuvants

Abstract

As prophylactic vaccine adjuvants for infectious diseases, cyclic dinucleotides (CDNs) induce safe, potent, long-lasting humoral and cellular memory responses in the systemic and mucosal compartments. As therapeutic cancer vaccine adjuvants, CDNs induce potent anti-tumor immunity, including cytotoxic T cells and NK cells activation that achieve durable regression in multiple mouse models of tumors. Clinical trials are ongoing to fulfill the promise of CDNs (ClinicalTrials.gov: NCT02675439, NCT03010176, NCT03172936, and NCT03937141). However, in October 2018, the first clinical data with Merck’s CDN MK-1454 showed zero activity as a monotherapy in patients with solid tumors or lymphomas (NCT03010176). Lately, the clinical trial from Aduro’s CDN ADU-S100 monotherapy was also disappointing (NCT03172936). The emerging hurdle in CDN vaccine development calls for a timely re-evaluation of our understanding on CDN vaccine adjuvants. Here, we review the status of CDN vaccine adjuvant research, including their superior adjuvant activities, in vivo mode of action, and confounding factors that affect their efficacy in humans. Lastly, we discuss the strategies to overcome the hurdle and advance promising CDN adjuvants in humans.

A cGAMP-containing hydrogel for prolonged SARS-CoV-2 RBD subunit vaccine exposure induces a broad and potent humoral response

“…cDC2s, while also able to cross-present, present their antigen on MHC II molecules and are thus the main activators of helper T cells (Th cells), which in turn are crucial for activation of both CTL and the humoral response mediated by antibody-producing B cells. [11, 19]…”

“…[17] Employing non-hydrolyzable cGAMP analogs as effective and safe vaccine adjuvants is even more challenging due to the lack of an immunological niche equivalent to the tumor microenvironment, as well as their poor pharmacokinetics and pharmacodynamics. [18] [19] We propose to harness natural cGAMP as a safe and effective adjuvant using a hydrogel depot technology that localizes and sustains low but steady cGAMP and antigen concentrations which also serves as an immunological niche; any cGAMP leaked out of the niche should be rapidly degraded by ENPP1 without causing any systemic interferon responses.…”

STINGing the Tumor Microenvironment to Promote Therapeutic Tertiary Lymphoid Structure Development

“…ADU-S100/MIW815 (NCT02675439), MK-1454 (NCT03010176)] as monotherapies has provided some evidence for pro-inflammatory changes in the TME or patient sera, therapeutic benefits have been minimal (i.e. < 5% objective response rate) in early phase clinical trials treating advanced-stage cancer patients (as described in greater detail in a series of recent outstanding reviews) ( 55 , 116 , 117 ). This deficiency may be circumvented by the provision of next-generation, systemic STING agonists for more effective treatment of patients with multifocal, disseminated disease in visceral tissue sites.…”

Cyclic Guanosine Monophosphate–Adenosine Monophosphate Synthase (cGAS), a Multifaceted Platform of Intracellular DNA Sensing

“…Molecular dynamics simulations comparing human and mouse STING conformations (opened-inactive or closed-active) have been instrumental in describing the species-specificity of STING in an Apo conformation or upon binding to the DMXAA agonist ( 49 ). This species-specificity must be taken into account when considering the applicability of the results obtained for STING agonists using mouse models before they enter into clinical trials ( 50 ). At the molecular level, the modulation of STING functions occurs through palmitoylation ( 51 ), protein multimerization, and translocation from ER to Golgi ( 52 , 53 ) for the recruitment of downstream signaling partners ( 13 ).…”