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.

Keywords: anti-tumor immunity; cyclic dinucleotides; vaccine adjuvants.

Figure 1

The mode of action of cyclic dinucleotides (CDNs) in dendritic cells (DCs). Immunized CDNs are taken up by pinocytosis or phagocytosis by dendritic cells in vivo. In the cytoplasm, CDNs bind to STING dimers located on the endoplasmic reticulum (ER) membrane, which undergoes conformational changes and activation. The STING (Stimulator of interferon genes) activation recruits kinases TANK binding kinase 1 (TBK 1) or IκB kinase (Iκκε). TBK 1 phosphorylates interferon regulatory factor 3 (IRF3), which dimerizes and translocates to the nucleus to activate type I IFNs. Iκκε phosphorylates nuclear factor-κB (NF-κB) inhibitor IκBα leading to dissociation of IκBα from NF-κB and translocation of the later to the nucleus to activate pro-inflammatory cytokines such as TNF-α.

Figure 2

Cellular mechanism of CDN adjuvanticity by lung DCs. Intranasal immunization of CDN promotes its uptake by functionally distinct lung DC subsets: cDC1, TNFR2⁺ cDC2, and TNFR2^- cDC2. Upon the CDN uptake, cDC1 and TNFR2⁺ cDC2 mature and migrate towards the lung draining lymph node where they direct naïve T cells towards Th1, Th2, and Th17 effector cells. The TNFR2^- cDC2 population, on the CDN uptake, is activated but does not migrate. Instead, the TNFR2^- cDC2 produces transmembrane TNF, which engages TNFR2 on monocyte-derived DCs (moDCs) to trigger lung moDCs activation. Activated lung moDCs induce Tfh, GC formation, and IgA production in the lung.

Figure 3

In vivo CDN-induced, type I IFNs-mediated anti-tumor immunity. The CDN immunization in the tumor microenvironment (TME) activates the STING pathway in DCs, endothelial cells, fibroblasts, and myeloid cells, leading to the production of type I IFNs. Type I IFNs act as a stimulus for DC to induce CD8⁺ T cell cross-priming. Type I IFNs also activate natural killer (NK) cells leading to NK cell-mediated cytotoxicity and tumor cell killing.