Biodegradable STING agonist nanoparticles for enhanced cancer immunotherapy.

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.

[1]  G. Barber,et al.  STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity , 2009, Nature.

[2]  Yoshihiro Hayakawa,et al.  STING is a direct innate immune sensor of cyclic-di-GMP , 2011, Nature.

[3]  C. Drake,et al.  Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. , 2012, The New England journal of medicine.

[4]  Jordan J. Green,et al.  Bioreducible Cationic Polymer-Based Nanoparticles for Efficient and Environmentally Triggered Cytoplasmic siRNA Delivery to Primary Human Brain Cancer Cells , 2014, ACS nano.

[5]  J. Lunceford,et al.  Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. , 2016, The Lancet. Oncology.

[6]  T. Gajewski,et al.  The host STING pathway at the interface of cancer and immunity. , 2016, The Journal of clinical investigation.

[7]  Yuan Wang,et al.  Polymeric Nanoparticles for Nonviral Gene Therapy Extend Brain Tumor Survival in Vivo , 2015, ACS nano.

[8]  Jordan J. Green,et al.  A bioreducible linear poly(β-amino ester) for siRNA delivery. , 2013, Chemical communications.

[9]  Nupura S. Bhise,et al.  The relationship between terminal functionalization and molecular weight of a gene delivery polymer and transfection efficacy in mammary epithelial 2-D cultures and 3-D organotypic cultures. , 2010, Biomaterials.

[10]  W. Grayson,et al.  Cystamine-terminated poly(beta-amino ester)s for siRNA delivery to human mesenchymal stem cells and enhancement of osteogenic differentiation. , 2012, Biomaterials.

[11]  George E. Katibah,et al.  Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity. , 2015, Cell reports.

[12]  Daniel G. Anderson,et al.  Small‐Molecule End‐Groups of Linear Polymer Determine Cell‐type Gene‐Delivery Efficacy , 2009, Advanced materials.

[13]  J. Sunshine,et al.  Effects of base polymer hydrophobicity and end-group modification on polymeric gene delivery. , 2011, Biomacromolecules.

[14]  D. Pardoll,et al.  Immune Checkpoint Inhibitors: Making Immunotherapy a Reality for the Treatment of Lung Cancer , 2013, Cancer Immunology Research.

[15]  L. Crinò,et al.  Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. , 2015, The New England journal of medicine.

[16]  Robert Langer,et al.  Degradable Poly(β-amino esters): Synthesis, Characterization, and Self-Assembly with Plasmid DNA , 2000 .

[17]  Daniel G. Anderson,et al.  Poly-beta amino ester-containing microparticles enhance the activity of nonviral genetic vaccines. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[18]  C. Drake,et al.  Immune checkpoint blockade: a common denominator approach to cancer therapy. , 2015, Cancer cell.

[19]  Robert Langer,et al.  Genetic engineering of human stem cells for enhanced angiogenesis using biodegradable polymeric nanoparticles , 2009, Proceedings of the National Academy of Sciences.

[20]  Nupura S. Bhise,et al.  Quantification of cellular and nuclear uptake rates of polymeric gene delivery nanoparticles and DNA plasmids via flow cytometry. , 2016, Acta biomaterialia.

[21]  R. Vonderheide,et al.  Mitigating the toxic effects of anticancer immunotherapy , 2014, Nature Reviews Clinical Oncology.

[22]  J. Sunshine,et al.  Non-viral gene delivery nanoparticles based on poly(β-amino esters) for treatment of glioblastoma. , 2011, Biomaterials.

[23]  Alfredo Quinones-Hinojosa,et al.  Continuous microfluidic assembly of biodegradable poly(beta-amino ester)/DNA nanoparticles for enhanced gene delivery. , 2017, Journal of biomedical materials research. Part A.

[24]  P. Sharma,et al.  The future of immune checkpoint therapy , 2015, Science.

[25]  J. Sunshine,et al.  Differential polymer structure tunes mechanism of cellular uptake and transfection routes of poly(β-amino ester) polyplexes in human breast cancer cells. , 2014, Bioconjugate chemistry.

[26]  E. Duh,et al.  Gene delivery nanoparticles specific for human microvasculature and macrovasculature. , 2012, Nanomedicine : nanotechnology, biology, and medicine.

[27]  S. Tzeng,et al.  Subtle Changes to Polymer Structure and Degradation Mechanism Enable Highly Effective Nanoparticles for siRNA and DNA Delivery to Human Brain Cancer , 2013, Advanced healthcare materials.

[28]  J. Sunshine,et al.  Uptake and transfection with polymeric nanoparticles are dependent on polymer end-group structure, but largely independent of nanoparticle physical and chemical properties. , 2012, Molecular pharmaceutics.

[29]  J. Wolchok,et al.  Combination immunotherapy: a road map , 2017, Journal of Immunotherapy for Cancer.

[30]  A. Ravaud,et al.  Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. , 2015, The New England journal of medicine.

[31]  David C. Smith,et al.  Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  D. Kanne,et al.  Rationale, progress and development of vaccines utilizing STING-activating cyclic dinucleotide adjuvants , 2013, Therapeutic advances in vaccines.

[33]  J. Sunshine,et al.  The effect and role of carbon atoms in poly(β-amino ester)s for DNA binding and gene delivery. , 2013, Journal of the American Chemical Society.

[34]  D. Pardoll,et al.  STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade , 2015, Science Translational Medicine.

[35]  M. Pomper,et al.  Polymeric nanoparticles as cancer-specific DNA delivery vectors to human hepatocellular carcinoma. , 2017, Journal of controlled release : official journal of the Controlled Release Society.