Designer vaccine nanodiscs for personalized cancer immunotherapy



Despite the tremendous potential of peptide-based cancer vaccines, their efficacy has been limited in humans. Recent innovations in tumour exome sequencing have signalled the new era of personalized immunotherapy with patient-specific neoantigens, but a general methodology for stimulating strong CD8α+ cytotoxic T-lymphocyte (CTL) responses remains lacking. Here we demonstrate that high-density lipoprotein-mimicking nanodiscs coupled with antigen (Ag) peptides and adjuvants can markedly improve Ag/adjuvant co-delivery to lymphoid organs and sustain Ag presentation on dendritic cells. Strikingly, nanodiscs elicited up to 47-fold greater frequencies of neoantigen-specific CTLs than soluble vaccines and even 31-fold greater than perhaps the strongest adjuvant in clinical trials (that is, CpG in Montanide). Moreover, multi-epitope vaccination generated broad-spectrum T-cell responses that potently inhibited tumour growth. Nanodiscs eliminated established MC-38 and B16F10 tumours when combined with anti-PD-1 and anti-CTLA-4 therapy. These findings represent a new powerful approach for cancer immunotherapy and suggest a general strategy for personalized nanomedicine.

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Figure 1: Design of sHDL nanodisc platform for personalized cancer vaccines.
Figure 2: Strong and durable Ag presentation mediated by sHDL nanodiscs.
Figure 3: Vaccine nanodiscs for LN-targeting of Ag and adjuvants and elicitation of CTL responses.
Figure 4: Nanodisc-based neoantigen vaccination for personalized immunotherapy.
Figure 5: Tumour eradication by combination immunotherapy with multi-epitope vaccine nanodiscs and immune checkpoint blockade.


  1. 1

    Melief, C. J. & van der Burg, S. H. Immunotherapy of established (pre)malignant disease by synthetic long peptide vaccines. Nat. Rev. Cancer 8, 351–360 (2008).

    CAS  Article  Google Scholar 

  2. 2

    Speiser, D. E. et al. Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. J. Clin. Invest. 115, 739–746 (2005).

    CAS  Article  Google Scholar 

  3. 3

    Fourcade, J. et al. Immunization with analog peptide in combination with CpG and montanide expands tumor antigen-specific CD8+ T cells in melanoma patients. J. Immunother. 31, 781–791 (2008).

    CAS  Article  Google Scholar 

  4. 4

    Hailemichael, Y. et al. Persistent antigen at vaccination sites induces tumor-specific CD8+ T cell sequestration, dysfunction and deletion. Nat. Med. 19, 465–472 (2013).

    CAS  Article  Google Scholar 

  5. 5

    Reddy, S. T. et al. Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nat. Biotechnol. 25, 1159–1164 (2007).

    CAS  Article  Google Scholar 

  6. 6

    Moon, J. J. et al. Interbilayer-crosslinked multilamellar vesicles as synthetic vaccines for potent humoral and cellular immune responses. Nat. Mater. 10, 243–251 (2011).

    CAS  Article  Google Scholar 

  7. 7

    Lee, I. H. et al. Imageable antigen-presenting gold nanoparticle vaccines for effective cancer immunotherapy in vivo. Angew Chem. Int. Ed. 51, 8800–8805 (2012).

    CAS  Article  Google Scholar 

  8. 8

    Li, A. V. et al. Generation of effector memory T cell-based mucosal and systemic immunity with pulmonary nanoparticle vaccination. Sci. Transl. Med. 5, 204ra130 (2013).

    Google Scholar 

  9. 9

    Jeanbart, L. et al. Enhancing efficacy of anticancer vaccines by targeted delivery to tumor-draining lymph nodes. Cancer Immunol. Res. 2, 436–447 (2014).

    CAS  Article  Google Scholar 

  10. 10

    Xu, Z., Wang, Y., Zhang, L. & Huang, L. Nanoparticle-delivered transforming growth factor-beta siRNA enhances vaccination against advanced melanoma by modifying tumor microenvironment. ACS Nano 8, 3636–3645 (2014).

    CAS  Article  Google Scholar 

  11. 11

    Liu, H. et al. Structure-based programming of lymph-node targeting in molecular vaccines. Nature 507, 519–522 (2014).

    CAS  Article  Google Scholar 

  12. 12

    Rosalia, R. A. et al. CD40-targeted dendritic cell delivery of PLGA-nanoparticle vaccines induce potent anti-tumor responses. Biomaterials 40, 88–97 (2015).

    CAS  Article  Google Scholar 

  13. 13

    Chiu, Y. C., Gammon, J. M., Andorko, J. I., Tostanoski, L. H. & Jewell, C. M. Modular vaccine design using carrier-free capsules assembled from polyionic immune signals. ACS Biomater. Sci. Eng. 1, 1200–1205 (2015).

    CAS  Article  Google Scholar 

  14. 14

    Fan, Y. & Moon, J. J. Nanoparticle drug delivery systems designed to improve cancer vaccines and immunotherapy. Vaccines (Basel) 3, 662–685 (2015).

    CAS  Article  Google Scholar 

  15. 15

    Lizotte, P. H. et al. In situ vaccination with cowpea mosaic virus nanoparticles suppresses metastatic cancer. Nat. Nanotech. 13, 295–303 (2016).

    Article  Google Scholar 

  16. 16

    Yadav, M. et al. Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature 515, 572–576 (2014).

    CAS  Article  Google Scholar 

  17. 17

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

    CAS  Article  Google Scholar 

  18. 18

    Rajasagi, M. et al. Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. Blood 124, 453–462 (2014).

    CAS  Article  Google Scholar 

  19. 19

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

    CAS  Article  Google Scholar 

  20. 20

    Wolfrum, C. et al. Mechanisms and optimization of in vivo delivery of lipophilic siRNAs. Nat. Biotechnol. 25, 1149–1157 (2007).

    CAS  Article  Google Scholar 

  21. 21

    Fischer, N. O. et al. Colocalized delivery of adjuvant and antigen using nanolipoprotein particles enhances the immune response to recombinant antigens. J. Am. Chem. Soc. 135, 2044–2047 (2013).

    CAS  Article  Google Scholar 

  22. 22

    Duivenvoorden, R. et al. A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation. Nat. Commun. 5, 3065 (2014).

    Article  Google Scholar 

  23. 23

    Li, D., Gordon, S., Schwendeman, A. & Remaley, A. T. Apolipoprotein Mimetics in the Management of Human Disease 29–42 (Springer, 2015).

    Google Scholar 

  24. 24

    Khan, M., Lalwani, N., Drake, S., Crockatt, J. & Dasseux, J. Single-dose intravenous infusion of ETC-642, a 22-Mer ApoA-I analogue and phospholipids complex, elevates HDL-C in atherosclerosis patients. Circulation 108, 563–564 (2003).

    Article  Google Scholar 

  25. 25

    Miles, J. et al. Single-dose tolerability, pharmacokinetics, and cholesterol mobilization in HDL-C fraction following intravenous administration of ETC-642, a 22-mer ApoA-I analogue and phospholipids complex, in atherosclerosis patients. Proc. Arterioscler. Thromb. Vasc. Biol. 24, E19 (2004).

    Google Scholar 

  26. 26

    Kuai, R., Li, D., Chen, Y. E., Moon, J. J. & Schwendeman, A. High-density lipoproteins: Nature’s multifunctional nanoparticles. ACS Nano 10, 3015–3041 (2016).

    CAS  Article  Google Scholar 

  27. 27

    Alexis, F., Pridgen, E., Molnar, L. K. & Farokhzad, O. C. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol. Pharmacol. 5, 505–515 (2008).

    CAS  Article  Google Scholar 

  28. 28

    Anselmo, A. C. & Mitragotri, S. A review of clinical translation of inorganic nanoparticles. AAPS J. 17, 1041–1054 (2015).

    CAS  Article  Google Scholar 

  29. 29

    Hirosue, S., Kourtis, I. C., van der Vlies, A. J., Hubbell, J. A. & Swartz, M. A. Antigen delivery to dendritic cells by poly(propylene sulfide) nanoparticles with disulfide conjugated peptides: cross-presentation and T cell activation. Vaccine 28, 7897–7906 (2010).

    CAS  Article  Google Scholar 

  30. 30

    Saini, S. K. et al. Dipeptides promote folding and peptide binding of MHC class I molecules. Proc. Natl Acad. Sci. USA 110, 15383–15388 (2013).

    CAS  Article  Google Scholar 

  31. 31

    US National Library of Medicine [online] (2009); (Accessed 9 January 2015).

  32. 32

    US National Library of Medicine [online] (2008); (Accessed 9 January 2015).

  33. 33

    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).

    CAS  Article  Google Scholar 

  34. 34

    Zou, W., Wolchok, J. D. & Chen, L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci. Transl. Med. 8, 328rv324 (2016).

    Article  Google Scholar 

  35. 35

    Verdegaal, E. M. et al. Neoantigen landscape dynamics during human melanoma–T cell interactions. Nature 536, 91–95 (2016).

    CAS  Article  Google Scholar 

  36. 36

    Moynihan, K. D. et al. Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses. Nat. Med. (2016).

  37. 37

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

    CAS  Article  Google Scholar 

  38. 38

    Kang, T. H. et al. Chemotherapy acts as an adjuvant to convert the tumor microenvironment into a highly permissive state for vaccination-induced antitumor immunity. Cancer Res. 73, 2493–2504 (2013).

    CAS  Article  Google Scholar 

  39. 39

    Gubin, M. M. et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515, 577–581 (2014).

    CAS  Article  Google Scholar 

  40. 40

    Robbins, P. F. et al. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat. Med. 19, 747–752 (2013).

    CAS  Article  Google Scholar 

  41. 41

    Linnemann, C. et al. High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4 + T cells in human melanoma. Nat. Med. 21, 81–85 (2015).

    CAS  Article  Google Scholar 

  42. 42

    Kuai, R. et al. Efficient delivery of payload into tumor cells in a controlled manner by TAT and thiolytic cleavable PEG co-modified liposomes. Mol. Pharmacol. 7, 1816–1826 (2010).

    CAS  Article  Google Scholar 

  43. 43

    Lutz, M. B. et al. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J. Immunol. Methods 223, 77–92 (1999).

    CAS  Article  Google Scholar 

  44. 44

    DeMuth, P. C., Moon, J. J., Suh, H., Hammond, P. T. & Irvine, D. J. Releasable layer-by-layer assembly of stabilized lipid nanocapsules on microneedles for enhanced transcutaneous vaccine delivery. ACS Nano 6, 8041–8051 (2012).

    CAS  Article  Google Scholar 

  45. 45

    Gorrin-Rivas, M. J. et al. Mouse macrophage metalloelastase gene transfer into a murine melanoma suppresses primary tumor growth by halting angiogenesis. Clin. Cancer Res. 6, 1647–1654 (2000).

    CAS  Google Scholar 

  46. 46

    Ochyl, L. J. & Moon, J. J. Whole-animal imaging and flow cytometric techniques for analysis of antigen-specific CD8+ T cell responses after nanoparticle vaccination. J. Vis. Exp. 98, e52771 (2015).

    Google Scholar 

  47. 47

    Fan, Y., Sahdev, P., Ochyl, L. J., J, J. A. & Moon, J. J. Cationic liposome-hyaluronic acid hybrid nanoparticles for intranasal vaccination with subunit antigens. J. Control Release 208, 121–129 (2015).

    CAS  Article  Google Scholar 

  48. 48

    Ning, N. et al. Cancer stem cell vaccination confers significant antitumor immunity. Cancer Res. 72, 1853–1864 (2012).

    CAS  Article  Google Scholar 

  49. 49

    Stephan, M. T., Moon, J. J., Um, S. H., Bershteyn, A. & Irvine, D. J. Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nat. Med. 16, 1035–1041 (2010).

    CAS  Article  Google Scholar 

  50. 50

    Anthony, D. D. & Lehmann, P. V. T-cell epitope mapping using the ELISPOT approach. Methods 29, 260–269 (2003).

    CAS  Article  Google Scholar 

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This work was supported in part by the NIH (R01GM113832, A.S.; R21NS091555, A.S.; UL1TR000433, J.J.M.; 1K22AI097291, J.J.M.; R01EB022563, J.J.M.; R01AI127070, J.J.M.), AHA (13SDG17230049, A.S.), UM MTRAC for Life Sciences (A.S.), and the UM College of Pharmacy faculty start-up fund (J.J.M., A.S.). J.J.M. is a Young Investigator supported by the Melanoma Research Alliance (348774), DoD/CDMRP Peer Reviewed Cancer Research Program (W81XWH-16-1-0369), and NSF CAREER Award (1553831). R.K. is supported by the Broomfield International Student Fellowship and the AHA Pre-doctoral Fellowship (15PRE25090050). L.J.O. is supported by pre-doctoral fellowships from UM Rackham and AFPE. We acknowledge J. Whitfield for his technical assistance with ELISPOT and thank R. H. Lyons, L. V. Diaz, J. K. Kim and P. H. Krebsbach for their contributions to cDNA sequencing. We acknowledge D. J. Irvine (MIT) and N. A. Kotov (UM) for critical review of the manuscript; the University of Michigan Consulting for Statistics, Computing, and Analytics Research (CSCAR) for help with statistical analyses; G. Skiniotis and A. Dosey (UM) for their aid with transmission electron microscopy; the NIH Tetramer Core Facility (contract HHSN272201300006C) for provision of MHC-I tetramers; N. Shastri (University of California, Berkeley) for B3Z T-cell hybridoma; K. Rock (University of Massachusetts, Amherst, Massachusetts) for B16OVA cells; and W. Zou (University of Michigan, Ann Arbor, Michigan) for MC-38 cells. Opinions interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense.

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R.K., A.S. and J.J.M. designed the experiments. R.K. performed the experiments. L.J.O. contributed to the tetramer staining assays. R.K., A.S. and J.J.M. analysed the data and K.S.B. aided in the interpretation of data. R.K. and J.J.M. wrote the paper.

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Correspondence to Anna Schwendeman or James J. Moon.

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Competing interests

A patent application for nanodisc vaccines has been filed, with J.J.M., A.S. and R.K. as inventors, and J.J.M. and A.S. are co-founders of EVOQ Therapeutics, LLC., that develops the nanodisc technology for vaccine applications.

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Kuai, R., Ochyl, L., Bahjat, K. et al. Designer vaccine nanodiscs for personalized cancer immunotherapy. Nature Mater 16, 489–496 (2017).

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