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

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.

Development of Extracellular Vesicle Therapeutics: Challenges, Considerations, and Opportunities

“…Ventures in treatments for dermatological disorders and skin repair (Aegle Therapeutics, XOStem Inc., Exogenus Therapeutics), as well as cancer (Aethlon Medical, Unicyte AG, TAVEC Pharmaceuticals, Puretech Health, EV Therapeutics Inc., Anjarum Biosciences, Codiak Biosciences) and neurological disorders/diseases (Stemcell Medicine Ltd., Puretech Health, Evox Therapeutics, Codiak Biosciences) dominate the commercial EV-based therapeutic landscape. Codiak Biosciences have identified two EV-associated membrane proteins (internal/lumen or external orientated), which they use as scaffolds to link molecules of interest and engineer EVs for therapeutic application; this engineering platform (engEx TM ) has been utilized to develop exoSTING (EVs enriched in stimulator of interferon genes in the lumen) ( Jang et al, 2021 ), and exoIL12 ( Lewis et al, 2021 ), currently in Phase 1/2 clinical trial (NCT04592484). Significant efforts in other areas include wound healing (RION Health), metabolic disorders (Evox Therapeutics), fibrotic and immunological conditions (Puretech Health), acute respiratory distress syndrome (Direct Biologics), kidney and liver disease (Unicyte AG), and inflammation (Direct Biologics, Cell-Factory BVBA, Puretech Health).…”

Therapeutic Potential of Nucleic Acids when Combined with Extracellular Vesicles

“…Additionally, cells overexpressing prostaglandin F2 Receptor negative regulator (PTGFRN), a common EV surface protein and immune activator, produced EVs rich in PTGFRN. The PTGFRN rich HEK293T EVs, termed ExoSTING, were subsequently isolated and co-cultured with cyclic dinucleotides (CDN) for 24 hours resulting in increased CDN tumor immune surveillance efficacy [ 142 ]. This preclinical study provides early evidence of the synergistic effects of PTGFRN EVs loaded with cyclic dinucleotides and recently advanced into a Phase 1/2 study [ 142 ].…”

“…The PTGFRN rich HEK293T EVs, termed ExoSTING, were subsequently isolated and co-cultured with cyclic dinucleotides (CDN) for 24 hours resulting in increased CDN tumor immune surveillance efficacy [ 142 ]. This preclinical study provides early evidence of the synergistic effects of PTGFRN EVs loaded with cyclic dinucleotides and recently advanced into a Phase 1/2 study [ 142 ]. Passive loading provides a high-throughput and non-invasive method of loading EVs and further studies should elucidate the protection capacity of EVs when the therapeutics are associated to the external surface of the EVs.…”

“…Looking ahead, a similar study will be conducted in patients with early-stage cutaneous T cell lymphoma. Building on preclinical findings [ 142 ], CDK-002, PTGFRN rich EVs loaded with CDNs will be administrated intratumorally in subjects with advanced/metastatic, recurrent, injectable tumors with emphasis on head and neck squamous cell cancer, triple negative breast cancer, anaplastic thyroid carcinoma and cutaneous squamous cell carcinoma. This open label Phase ½ multicenter study focuses on dose escalation, safety, pharmacodynamics and PK (NCT04592484).…”

Investigating the in vivo biodistribution of extracellular vesicles isolated from various human cell sources using positron emission tomography

“…Engineering EVs for cancer therapies are among the most promising therapeutics undergoing clinical trials (ClinicalTrials.gov identifiers: NCT05156229, NCT04592484). [48][49][50] Utilizing PET approaches in humans would be ideal for understanding the biodistribution of EVs over time, which is an essential requirement for successfully developing drug delivery platforms. Understanding the pharmacokinetic profile through noninvasive imaging informs tumor uptake and off-target targeting toxicity concerns, which can be used to design more effective, safer therapeutics and accelerate translation.…”