Biodegradable STING agonist nanoparticles for enhanced cancer immunotherapy

David R Wilson; Rupashree Sen; Joel C Sunshine; Drew M Pardoll; Jordan J Green; Young J Kim

doi:10.1016/j.nano.2017.10.013

Biodegradable STING agonist nanoparticles for enhanced cancer immunotherapy

Nanomedicine. 2018 Feb;14(2):237-246. doi: 10.1016/j.nano.2017.10.013. Epub 2017 Nov 7.

Authors

David R Wilson¹, Rupashree Sen², Joel C Sunshine¹, Drew M Pardoll³, Jordan J Green⁴, Young J Kim⁵

Affiliations

¹ Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Institute for Nanobiotechnology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Materials Science and Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Chemical and Biomolecular Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: [email protected].
⁵ Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Otolaryngology / Head & Neck Surgery, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: [email protected].

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.

Keywords: Cancer immunotherapy; PBAE nanoparticle formulation; STING agonist.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / administration & dosage*
Antineoplastic Agents / chemistry
Female
Immunotherapy*
Interferon Regulatory Factor-3 / metabolism
Melanoma, Experimental / immunology
Melanoma, Experimental / therapy*
Membrane Proteins / agonists*
Mice
Mice, Inbred C57BL
Nanoparticles / administration & dosage*
Nanoparticles / chemistry
Nucleotides, Cyclic / administration & dosage*
Nucleotides, Cyclic / chemistry
Polymers / chemistry
Tumor Cells, Cultured

Substances

Antineoplastic Agents
IRF3 protein, human
Interferon Regulatory Factor-3
Membrane Proteins
Nucleotides, Cyclic
Polymers
STING1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding