Designer vaccine nanodiscs for personalized cancer immunotherapy

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Abstract

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.

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Acknowledgements

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.

Corresponding authors

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). https://doi.org/10.1038/nmat4822

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