Feature Article
Biodegradable STING agonist nanoparticles for enhanced cancer immunotherapy

https://doi.org/10.1016/j.nano.2017.10.013Get rights and content

Abstract

Therapeutic cancer vaccines require adjuvants leading to robust type I interferon and proinflammatory cytokine responses in the tumor microenvironment to induce an anti-tumor response. Cyclic dinucleotides (CDNs), a potent Stimulator of Interferon Receptor (STING) agonist, are currently in phase I trials. However, their efficacy may be limited to micromolar concentrations due to the cytosolic residence of STING in the ER membrane. Here we utilized biodegradable, poly(beta-amino ester) (PBAE) nanoparticles to deliver CDNs to the cytosol leading to robust immune response at >100-fold lower extracellular CDN concentrations in vitro. The leading CDN PBAE nanoparticle formulation induced a log-fold improvement in potency in treating established B16 melanoma tumors in vivo when combined with PD-1 blocking antibody in comparison to free CDN without nanoparticles. This nanoparticle-mediated cytosolic delivery method for STING agonists synergizes with checkpoint inhibitors and has strong potential for enhanced cancer immunotherapy.

Graphical Abstract

While cyclic dinucleotides (CDNs; STING agonists) are potent IFN inducing agents, these adjuvants have a narrow therapeutic window partly due to their inability to efficiently bypass the cellular membrane. The net negative charge of CDNs limits their cytosolic bioavailability and interaction with the cytosolic protein STING, necessitating micromolar extracellular concentrations for effective activation. Here, we demonstrate the utilization of biodegradable, cationic polymeric nanoparticles for cytosolic delivery of CDNs to professional antigen presenting cells for log-fold improved adjuvant activity in vitro and in vivo.

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Section snippets

Chemicals

All chemicals were of analytical grade and obtained from Sigma Aldrich Chemicals (St Louis, MO, USA). RPMI 1640 medium (Gibco BRL, Grand Island, NY, USA), fluorochrome conjugated antibodies (BD Biosciences, San Jose, CA, USA), MTT Aqueous One cell viability kit (Promega, Madison, WI, USA) were used without modification. Cyclic dinucleotides were provided by Aduro Biotech (Berkeley, CA, USA). QUANTI-blue and THP1-ISG cells were purchased from Invivogen (San Diego, CA, USA). Monocyte isolation

CDNs are potent activators of IRF3 at micromolar doses

Recent publications have shown CDNs to be potent activators of the adaptive immune system via activation of type I IFN and proinflammatory cytokine response leading to potent efficacy in multiple models of established cancer.1 As a result, we selected the CDNs shown in Figure 1, A to act as adjuvant molecules for studies in vitro. ML-RR-CDA is a modified version of cyclic-di-AMP formulated for increased in vivo stability and human STING activation, while RR-CDG was a phosphodiesterase resistant

Discussion

CDNs are highly potent adjuvants that can impact clinical cancer immunotherapy, leading to robust activation of the IRF3 transcription factor through STING, which is capable of triggering tumor regression when activated in the right context.1, 26, 31 With promising pre-clinical results reported to date, CDNs are currently under investigation in the FDA Phase I clinical trials for advanced metastatic solid tumors and lymphomas (NCT02675439) by Aduro Biotech working with Novartis to determine the

Acknowledgment

The authors thank Dr. Kristen Kozielski for the synthesis of polymer PBAE R647 used in the screening study.

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    Funding support: The authors thank the NIH for support of this research (NIH R01EB016721, R01EB022148, and R01CA195503; Wilmer Core Grant (5P30EY001765); NIH S10 OD016374; NIH R01CA178613). The authors thank the Bloomberg-Kimmel Institute for Cancer Immunotherapy for support and thank the Johns Hopkins University for support from a Discovery Award. DRW thanks the NSF for a Graduate Research Fellowship (DGE-0707427). YJK thanks the Baker Lab for support.

    1

    These authors contributed equally to this work.

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