Liposomal Delivery Enhances Immune Activation by STING Agonists for Cancer Immunotherapy

Abstract

Overcoming the immunosuppressive tumor microenvironment (TME) is critical to realizing the potential of cancer immunotherapy strategies. Agonists of stimulator of interferon genes (STING), a cytosolic immune adaptor protein, have been shown to induce potent anti-tumor activity when delivered into the TME. However, the anionic properties of STING agonists make them poorly membrane permeable, and limit their ability to engage STING in the cytosol of responding cells. In this study, cationic liposomes with varying surface polyethylene glycol (PEG) levels were used to encapsulate cGAMP to facilitate its cytosolic delivery. In vitro studies with antigen-presenting cells (APCs) revealed that liposomal formulations substantially improved the cellular uptake of cGAMP and pro-inflammatory gene induction relative to free drug. Liposomal encapsulation allowed cGAMP delivery to metastatic melanoma tumors in the lung, leading to anti-tumor activity, whereas free drug produced no effect at the same dose. Injection of liposomal cGAMP into orthotopic melanoma tumors showed retention of cGAMP at the tumor site and co-localization with tumor-associated APCs. Liposomal delivery induced regression of injected tumors and produced immunological memory that protected previously treated mice from rechallenge with tumor cells. These results show that liposomal delivery improves STING agonist activity, and could improve their utility in clinical oncology.

A robust microparticle platform for a STING-targeted adjuvant that enhances both humoral and cellular immunity during vaccination

“…This is consistent with previous studies that attempted to encapsulate other hydrophilic cargo within PLGA MPs using similar emulsion methods [63, 64]. Compared to other reported CDN delivery vehicles (polymeric hydrogel particles (47%) [42] or liposomes (2 to 35%) [41, 43–45]), electrospray was able to achieve a significantly superior CDN EE (90%). This multi-fold increase in EE has promising manufacturing implications for using this electrospray platform to formulate hydrophilic, small molecule CDNs.…”

Modulating Elasticity of Liposome for Enhanced Cancer Immunotherapy

“…cGAMP, selected as an immune response model agonist, and 5′-GMP were then encapsulated into liposomes via thin film rehydration and membrane extrusion to form sub-200 nm sized Lipo-NPs. The encapsulation efficiency of cGAMP was 22.6%, consistent with previous reports . To fabricate liposomes with different elasticities, three identical liposome suspensions were treated with distinct concentrations of Zn­(NO 3 ) 2 , cross-linking the cGAMP and 5′-GMP encapsulated cores.…”

A robust microparticle platform for a STING-targeted adjuvant that enhances both humoral and cellular immunity during vaccination

“…This is consistent with previous studies that attempted to encapsulate other hydrophilic cargo within PLGA MPs using similar emulsion methods [63,64]. Compared to other reported CDN delivery vehicles (polymeric hydrogel particles (47%) [42] or liposomes (2 to 35%) [41,[43][44][45]), electrospray was able to achieve a significantly superior CDN EE (90%). This multi-fold increase in EE has promising manufacturing implications for using this electrospray platform to formulate hydrophilic, small molecule CDNs.…”