Delivery of Stimulator of Interferon Genes (STING) Agonist Using Polypeptide‐Modified Dendrimer Nanoparticles in the Treatment of Melanoma

Abstract

Using the innate immune system to instigate an antitumor response is an increasingly attractive approach in cancer immunotherapy. Engagement of pathogenassociated molecular patterns (PAMPs) with their respective pattern recognition receptors (PRRs) was reported to elicit robust downstream endogenous cytokine production and immune cell activation, which is responsible for the potent immune responses generated by vaccines and against tumors. Cyclic dinucleotides (CDNs), such as the second messenger 2 03 0-cyclic guanosine monophosphate-adenosine monophosphate (cGMP-AMP or cGAMP), are a class of PAMPs that are generated upon sensing cytosolic DNA. The production of cGAMP leads to agonism of stimulator of interferon genes (STING), enacting a type-I interferon (IFN-I)-driven proinflammatory program including the stimulation of dendritic cells (DCs) and cross-presentation of tumor antigens to T-cells, thereby priming them for antitumor effector functionality. This bridge between innate and adaptive antitumor immunity positions STING as a critical regulator of immunosurveillance, reinforced by studies in STING-deficient mice highlighting increased susceptibility to tumorigenesis and diminished responsiveness to immunotherapy such as immune checkpoint inhibitors (ICIs). The role of STING signaling in antitumor responses as well as insufficient endogenous agonism has prompted investigations into exogenous cGAMP and structural analogs as therapeutics to promote antitumor immunity. Intratumoral (IT) injection of CDNs has reached phase I clinical trials; however, CDNs are anionic and highly hydrophilic, which restricts their entry into the cytoplasm where STING resides. Consequently, CDNs have transient interactions with immune cells (e.g., DCs, macrophages) in the tumor microenvironment (TME) and are rapidly eliminated from the tumor site. Biomaterial-based delivery strategies can be leveraged to improve internalization into cells, therefore augmenting the activity of adjuvants such as STING agonists. Indeed, it has previously been demonstrated that using nanoparticles (NPs) of lipidic or polymeric origin to encapsulate CDNs can Dr. P. Dosta, Dr. A. M. Cryer, M. Prado, M. Z. Dion, Dr. S. Ferber, Dr. S. Kalash, Dr. N. Artzi Institute for Medical Engineering and Science Massachusetts Institute of Technology Cambridge, MA 02139, USA E-mail: [email protected], [email protected] Dr. P. Dosta, Dr. A. M. Cryer, M. Prado, M. Z. Dion, Dr. S. Ferber, Dr. S. Kalash, Dr. N. Artzi Department of Medicine Division of Engineering in Medicine Brigham and Women’s Hospital Harvard Medical School Boston, MA 02115, USA