Au naturale: use of biologically derived cyclic di-nucleotides for cancer immunotherapy

Abstract

Cyclic di-nucleotides (CDNs) are widespread second messenger signalling molecules that regulate fundamental biological processes across the tree of life. These molecules are also potent modulators of the immune system, inducing a Type I interferon response upon binding to the eukaryotic receptor STING. Such a response in tumours induces potent immune anti-cancer responses and thus CDNs are being developed as a novel cancer immunotherapy. In this review, I will highlight the use, challenges and advantages of using naturally occurring CDNs to treat cancer.

Amphiphilic Block Copolymer Nanostructures as a Tunable Delivery Platform: Perspective and Framework for the Future Drug Product Development

“…204,205,207,208 It has been speculated that poor cellular uptake or degradation by extracellular enzymes, possibly the mammalian ecto-nucleotide phosphodiesterase (ENPP1) that hydrolyses cGAMP, may limit its efficacy. 209,210 To address this problem, the use of nanocarriers for efficient delivery of cdGMP to the lymph nodes or to trigger NK cell killing of murine melanoma have been reported. 206,211 In summary, based on existing evidence in the literature and the results of our experiments, we believe one key mechanism by which the ATP vaccine induces a superior adaptive immune response is the targeted delivery of antigen to DCs that results in efficient antigen presentation.…”

“…In view of its immunostimulatory ability, cdGMP has been used successfully in preclinical studies as a vaccine adjuvant , or as a cancer therapeutic. − However, subcutaneous administration of cdGMP is associated with poor uptake by the draining lymph nodes and is instead systemically disseminated, leading to generalized inflammation . Additionally, direct injection into tumors did not consistently generate an antitumor effect. ,,, It has been speculated that poor cellular uptake or degradation by extracellular enzymes, possibly the mammalian ecto-nucleotide phosphodiesterase (ENPP1) that hydrolyses cGAMP, may limit its efficacy. , To address this problem, the use of nanocarriers for efficient delivery of cdGMP to the lymph nodes or to trigger NK cell killing of murine melanoma have been reported. , …”

Development of a 3’3’‐Cyclic GMP‐AMP Enzyme Linked Immunoassay Reveals Phage Infection Reduces DncV Activity

“…Thus far, commercial ELISAs have been developed to detect 3'3'cyclic di-GMP, 3'3'-cyclic di-AMP, and 2'3'-cyclic GMP-AMP, a CDN that induces anti-viral and anti-cancer immune responses in metazoans. [26] A similar ELISA has not been developed to detect 3'3'-cGAMP and specifically to discriminate this CDN from 2'3'-cGAMP.…”