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Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy

Nature Nanotechnology volume 12, pages 877–882 (2017)Cite this article

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An Author Correction to this article was published on 12 February 2021

This article has been updated

Abstract

Immunotherapy holds tremendous promise for improving cancer treatment1. To administer radiotherapy with immunotherapy has been shown to improve immune responses and can elicit the ‘abscopal effect’2. Unfortunately, response rates for this strategy remain low3. Herein we report an improved cancer immunotherapy approach that utilizes antigen-capturing nanoparticles (AC-NPs). We engineered several AC-NP formulations and demonstrated that the set of protein antigens captured by each AC-NP formulation is dependent on the NP surface properties. We showed that AC-NPs deliver tumour-specific proteins to antigen-presenting cells (APCs) and significantly improve the efficacy of αPD-1 (anti-programmed cell death 1) treatment using the B16F10 melanoma model, generating up to a 20% cure rate compared with 0% without AC-NPs. Mechanistic studies revealed that AC-NPs induced an expansion of CD8+ cytotoxic T cells and increased both CD4+T/Treg and CD8+T/Treg ratios (Treg, regulatory T cells). Our work presents a novel strategy to improve cancer immunotherapy with nanotechnology.

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Figure 1: Schematic depiction of utilizing AC-NPs to improve cancer immunotherapy.
Figure 2: The capture of cancer-derived proteins by AC-NPs is dependent on their surface chemistry.
Figure 3: AC-NPs can improve immunotherapy and the abscopal effect in B16-F10 xenografts.
Figure 4: AC-NPs facilitate antigen uptake by APCs and increase immune activation.
Figure 5: TDPA-coated AC-NPs enhance the efficacy of immunotherapy based on cancer vaccination.

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References

  1. Couzin-Frankel, J. Breakthrough of the year 2013. Cancer immunotherapy. Science 342, 1432–1433 (2013).

    CAS  Google Scholar 

  2. Postow, M. A. et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 366, 925–931 (2012).

    Article  CAS  Google Scholar 

  3. Twyman-Saint Victor, C. et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373–377 (2015).

    Article  CAS  Google Scholar 

  4. McNutt, M. Cancer immunotherapy. Science 342, 1417 (2013).

    Article  CAS  Google Scholar 

  5. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    Article  CAS  Google Scholar 

  6. Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).

    Article  CAS  Google Scholar 

  7. Hamid, O. et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369, 134–144 (2013).

    Article  CAS  Google Scholar 

  8. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    Article  CAS  Google Scholar 

  9. Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    Article  CAS  Google Scholar 

  10. Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).

    Article  CAS  Google Scholar 

  11. Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).

    Article  Google Scholar 

  12. Formenti, S. C. & Demaria, S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J. Natl Cancer Inst. 105, 256–265 (2013).

    Article  CAS  Google Scholar 

  13. Sharabi, A. B., Lim, M., DeWeese, T. L. & Drake, C. G. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol. 16, E498–E509 (2015).

    Article  Google Scholar 

  14. Chan, J. K. et al. Alarmins: awaiting a clinical response. J. Clin. Invest. 122, 2711–2719 (2012).

    Article  CAS  Google Scholar 

  15. Curtin, J. F. et al. HMGB1 mediates endogenous TLR2 activation and brain tumor regression. PLoS Med. 6, e10 (2009).

    Article  Google Scholar 

  16. Apetoh, L. et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat. Med. 13, 1050–1059 (2007).

    Article  CAS  Google Scholar 

  17. Fang, R. H., Kroll, A. V. & Zhang, L. Nanoparticle-based manipulation of antigen-presenting cells for cancer immunotherapy. Small 11, 5483–5496 (2015).

    Article  CAS  Google Scholar 

  18. Smith, D. M., Simon, J. K. & Baker, J. R. Jr Applications of nanotechnology for immunology. Nat. Rev. Immunol. 13, 592–605 (2013).

    Article  CAS  Google Scholar 

  19. Goldberg, M. S. Immunoengineering: how nanotechnology can enhance cancer immunotherapy. Cell 161, 201–204 (2015).

    Article  CAS  Google Scholar 

  20. Irvine, D. J., Hanson, M. C., Rakhra, K. & Tokatlian, T. Synthetic nanoparticles for vaccines and immunotherapy. Chem. Rev. 115, 11109–11146 (2015).

    Article  CAS  Google Scholar 

  21. Shao, K. et al. Nanoparticle-based immunotherapy for cancer. ACS Nano 9, 16–30 (2015).

    Article  CAS  Google Scholar 

  22. Kim, J. et al. Injectable, spontaneously assembling, inorganic scaffolds modulate immune cells in vivo and increase vaccine efficacy. Nat. Biotechnol. 33, 64–72 (2015).

    Article  CAS  Google Scholar 

  23. Jokerst, J. V., Lobovkina, T., Zare, R. N. & Gambhir, S. S. Nanoparticle PEGylation for imaging and therapy. Nanomedicine 6, 715–728 (2011).

    Article  CAS  Google Scholar 

  24. Kreiter, S. et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520, 692–696 (2015).

    Article  CAS  Google Scholar 

  25. Kardos, J. et al. Claudin-low bladder tumors are immune infiltrated and actively immune suppressed. JCI Insight 1, e85902 (2016).

    Article  Google Scholar 

  26. Gubin, M. M., Artyomov, M. N., Mardis, E. R. & Schreiber, R. D. Tumor neoantigens: building a framework for personalized cancer immunotherapy. J Clin. Invest. 125, 3413–3421 (2015).

    Article  Google Scholar 

  27. Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).

    Article  CAS  Google Scholar 

  28. Krysko, D. V. et al. Immunogenic cell death and DAMPs in cancer therapy. Nat. Rev. Cancer 12, 860–875 (2012).

    Article  CAS  Google Scholar 

  29. Bachmann, M. F. & Jennings, G. T. Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns. Nat. Rev. Immunol. 10, 787–796 (2010).

    Article  CAS  Google Scholar 

  30. Wang, C., Sun, W., Wright, G, Wang, A. Z. & Gu, Z. Inflammation-triggered cancer immunotherapy by programmed delivery of CpG and anti-PD1 antibody. Adv. Mater. 28, 8912–8920 (2016).

    Article  CAS  Google Scholar 

  31. Melief, C. J., van Hall, T., Arens, R., Ossendorp, F. & van der Burg, S. H. Therapeutic cancer vaccines. J. Clin. Invest. 125, 3401–3412 (2015).

    Article  Google Scholar 

  32. Govender, T., Stolnik, S., Garnett, M. C., Illum, L. & Davis, S. S. PLGA nanoparticles prepared by nanoprecipitation: drug loading and release studies of a water soluble drug. J. Control Release 57, 171–185 (1999).

    Article  CAS  Google Scholar 

  33. Zhang, L. et al. Self-assembled lipid--polymer hybrid nanoparticles: a robust drug delivery platform. ACS Nano 2, 1696–1702 (2008).

    Article  CAS  Google Scholar 

  34. Wisniewski, J. R., Zougman, A., Nagaraj, N. & Mann, M. Universal sample preparation method for proteome analysis. Nat. Methods 6, 359–362 (2009).

    Article  CAS  Google Scholar 

  35. Vizcaino, J. A. et al. 2016 Update of the PRIDE database and its related tools. Nucleic Acids Res. 44, 11033 (2016).

    Article  CAS  Google Scholar 

  36. Castle, J. C. et al. Exploiting the mutanome for tumor vaccination. Cancer Res. 72, 1081–1091 (2012).

    Article  CAS  Google Scholar 

  37. Dewan, M. Z. et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin. Cancer Res. 15, 5379–5388 (2009).

    Article  CAS  Google Scholar 

  38. Martinov, T. & Fife, B. T. Fractionated radiotherapy combined with PD-1 pathway blockade promotes CD8 T cell-mediated tumor clearance for the treatment of advanced malignancies. Ann. Transl. Med. 4, 82 (2016).

    Google Scholar 

Download references

Acknowledgements

The authors acknowledge D. Smalley at the Michael Hooker Proteomics Center for her assistance with mass spectrum data analysis (CA016086). The authors also acknowledge the University of North Carolina (UNC) Flow Cytometry Core Facility (P30 CA016086). The authors also thank our funding sources. A.Z.W., J.E.T., S.T. and J.M.D. are supported by funding from the National Institutes of Health (NIH)/National Cancer Institute (NCI) (U54CA198999, Carolina Center of Cancer Nanotechnology Excellence (CCNE) Nano Approaches to Modulate Host Cell Response for Cancer Therapy). B.V. is supported by funding from the UNC University Cancer Research Fund, Paul Calabresi Oncology K12 Award and a UNC CCNE Pilot Grant. A.Z.W. is also supported by funding from the NIH/NCI (U54 CA151652 and R01 CA178748) for this work. A.Z.W. was also supported by funding from the NIH/NCI (R21 CA182322). This work was also supported by a generous gift from E. and M. Barclay.

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Authors and Affiliations

  1. Laboratory of Nano- and Translational Medicine, Carolina Center for Cancer Nanotechnology Excellence, Carolina Institute of Nanomedicine, University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA

    Yuanzeng Min, Kyle C. Roche, Michael J. Eblan, Joseph M. Caster, Joel E. Tepper & Andrew Z. Wang

  2. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA

    Yuanzeng Min, Kyle C. Roche, Shaomin Tian, Michael J. Eblan, Karen P. McKinnon, Joseph M. Caster, Shengjie Chai, Joseph M. DeSimone, Joel E. Tepper, Benjamin G. Vincent, Jonathan S. Serody & Andrew Z. Wang

  3. Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA

    Yuanzeng Min, Kyle C. Roche, Michael J. Eblan, Joseph M. Caster, Joel E. Tepper & Andrew Z. Wang

  4. Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA

    Shaomin Tian, Karen P. McKinnon, Joseph M. DeSimone & Jonathan S. Serody

  5. Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA

    Shengjie Chai, Benjamin G. Vincent & Jonathan S. Serody

  6. Department of Pharmacology, UNC Proteomics Core Facility, University of North Carolina, Chapel Hill, 27599, North Carolina, USA

    Laura E. Herring

  7. Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China

    Longzhen Zhang & Andrew Z. Wang

  8. Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Tian Zhang

  9. Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, 27599, North Carolina, USA

    Joseph M. DeSimone

  10. Department of Chemistry, University of North Carolina, Chapel Hill, 27599, North Carolina, USA

    Joseph M. DeSimone

  11. Department of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, 27695, North Carolina, USA

    Joseph M. DeSimone

  12. Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, 10021, New York, USA

    Joseph M. DeSimone

Authors
  1. Yuanzeng Min
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Contributions

A.Z.W. and T.Z. conceived and designed the experiments with Y.M. and K.C.R. Y.M. and M.J.E. performed the efficacy study. Y.M. also performed the mechanistic study with the help of S.T. and K.P.M. L.H. processed all the raw mass spectrometry data. S.C. and B.G.V. analysed the mass spectrometry data for neoantigens. All authors analysed and discussed the data. A.Z.W., Y.M. and K.C.R. wrote the manuscript.

Corresponding author

Correspondence to Andrew Z. Wang.

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The authors declare no competing financial interests.

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Min, Y., Roche, K., Tian, S. et al. Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy. Nature Nanotech 12, 877–882 (2017). https://doi.org/10.1038/nnano.2017.113

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