ExoSTING, an extracellular vesicle loaded with STING agonists, promotes tumor immune surveillance

Su Chul Jang,Kevin Dooley,Kelvin Zhang,Douglas E Williams,William K Dahlberg,Kyriakos D Economides,Chang Ling Sia,Jorge Sanchez-Salazar,Nuruddeen D Lewis ,Scott Estes,Nikki L Ross,Marc Grenley,Joyoti Dey,Tong Zi,Christine Mccoy,Agata Villiger-Oberbek,Raymond J Moniz,Rane A Harrison,Ke Xu,Raymond W Bourdeau ,Joanne Y.h Lim ,Katherine Kirwin,Sriram Sathyanarayanan

doi:10.1038/s42003-021-02004-5

Su Chul Jang, Kevin Dooley + Show 21 more

Open Access

https://doi.org/10.1038/s42003-021-02004-5

Copy DOI

Abstract

Cyclic dinucleotide (CDN) agonists of the STimulator of InterferoN Genes (STING) pathway have shown immune activation and tumor clearance in pre-clinical models. However, CDNs administered intratumorally also promote STING activation leading to direct cytotoxicity of many cell types in the tumor microenvironment (TME), systemic inflammation due to rapid tumor extravasation of the CDN, and immune ablation in the TME. These result in a failure to establish immunological memory. ExoSTING, an engineered extracellular vesicle (EV) exogenously loaded with CDN, enhances the potency of CDN and preferentially activates antigen presenting cells in the TME. Following intratumoral injection, exoSTING was retained within the tumor, enhanced local Th1 responses and recruitment of CD8+ T cells, and generated systemic anti-tumor immunity to the tumor. ExoSTING at therapeutically active doses did not induce systemic inflammatory cytokines, resulting in an enhanced therapeutic window. ExoSTING is a novel, differentiated therapeutic candidate that leverages the natural biology of EVs to enhance the activity of CDNs.

Highlights

Cyclic dinucleotide (CDN) agonists of the STimulator of InterferoN Genes (STING) pathway have shown immune activation and tumor clearance in pre-clinical models
We hypothesized that extracellular vesicle (EV)-mediated delivery of CDN may significantly increase potency and preferential activation of antigen presenting cells (APCs) in the tumor microenvironment (TME)
We developed a methodology to purify a population of EVs stringently and reproducibly from large volumes of cell culture supernatant, similar to those recently reported by Jeppesen et al.[18]

Summary

Introduction

Cyclic dinucleotide (CDN) agonists of the STimulator of InterferoN Genes (STING) pathway have shown immune activation and tumor clearance in pre-clinical models. Activation of the STING pathway occurs by DNA recognition by cyclic guanosine monophosphate synthetase (cGAS) resulting in the generation of the cyclic dinucleotide (CDN) STING ligand 2′3′ cGAMP and is required for the generation of tumor-specific T cell responses, representing one mechanism of immune surveillance in the TME5. This effect is mediated by induction of cytokines, including type I interferons and chemokines[6]. The low membrane permeability, short residence time, and lack of specific uptake into antigen presenting cells (APCs) following

Objectives

Methods

Results

Conclusion