• An Erratum to this article was published on 03 June 2015

Abstract

Tumour-specific mutations are ideal targets for cancer immunotherapy as they lack expression in healthy tissues and can potentially be recognized as neo-antigens by the mature T-cell repertoire. Their systematic targeting by vaccine approaches, however, has been hampered by the fact that every patient’s tumour possesses a unique set of mutations (‘the mutanome’) that must first be identified. Recently, we proposed a personalized immunotherapy approach to target the full spectrum of a patient’s individual tumour-specific mutations1. Here we show in three independent murine tumour models that a considerable fraction of non-synonymous cancer mutations is immunogenic and that, unexpectedly, the majority of the immunogenic mutanome is recognized by CD4+ T cells. Vaccination with such CD4+ immunogenic mutations confers strong antitumour activity. Encouraged by these findings, we established a process by which mutations identified by exome sequencing could be selected as vaccine targets solely through bioinformatic prioritization on the basis of their expression levels and major histocompatibility complex (MHC) class II-binding capacity for rapid production as synthetic poly-neo-epitope messenger RNA vaccines. We show that vaccination with such polytope mRNA vaccines induces potent tumour control and complete rejection of established aggressively growing tumours in mice. Moreover, we demonstrate that CD4+ T cell neo-epitope vaccination reshapes the tumour microenvironment and induces cytotoxic T lymphocyte responses against an independent immunodominant antigen in mice, indicating orchestration of antigen spread. Finally, we demonstrate an abundance of mutations predicted to bind to MHC class II in human cancers as well by employing the same predictive algorithm on corresponding human cancer types. Thus, the tailored immunotherapy approach introduced here may be regarded as a universally applicable blueprint for comprehensive exploitation of the substantial neo-epitope target repertoire of cancers, enabling the effective targeting of every patient’s tumour with vaccines produced ‘just in time’.

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Acknowledgements

We thank M. Holzmann, A. König, U. Schmitt, R. Roth, C. Worm and N. Krause for technical assistance; L. Ralla, J. Groß, A. Spruß, M. Erdeljan, S. Wöll and C. Rohde for immunohistochemical staining and analysis; C. Paret for sequence validation of mutations; M. Brkic for immunofluorescence staining; S. Witzel and Bodo Tillmann, S. Wurzel and Z. Yildiz for cloning of constructs; S. Kind, M. Mechler, F. Wille, B. Otte and S. Petri for RNA production as well as L. Kranz and colleagues involved in RNA formulation development. We are grateful to B. Kloke, S. Heesch, A. Kuhn, J. Buck, C. Britten and H. Haas for conceptual and technical discussions. Moreover, we would like to thank V. Bukur, J. de Graf and C. Albrecht who supported the next-generation sequencing of samples. Furthermore we like to acknowledge A. Kong for critical reading and A. Orlandini for help with graphic design. The results shown here are in part based on data generated by the TCGA Research Network http://cancergenome.nih.gov/. The study was supported by the CI3 excellence cluster program of the Federal Ministry of Education and Research (BMBF).

Author information

Author notes

    • Mathias Vormehr
    •  & Niels van de Roemer

    These authors contributed equally to this work.

    • Özlem Türeci
    •  & Ugur Sahin

    These authors jointly supervised this work.

Affiliations

  1. TRON – Translational Oncology at the University Medical Center of Johannes Gutenberg University, Freiligrathstrasse 12, 55131 Mainz, Germany

    • Sebastian Kreiter
    • , Mustafa Diken
    • , Martin Löwer
    • , Jan Diekmann
    • , Sebastian Boegel
    • , Barbara Schrörs
    • , Fulvia Vascotto
    • , John C. Castle
    • , Arbel D. Tadmor
    • , Özlem Türeci
    •  & Ugur Sahin
  2. Research Center for Immunotherapy (FZI), Langenbeckstrasse 1, Building 708, 55131 Mainz, Germany

    • Mathias Vormehr
    • , Niels van de Roemer
    • , Christoph Huber
    •  & Ugur Sahin
  3. Biopharmaceutical New Technologies (BioNTech) Corporation, An der Goldgrube 12, 55131 Mainz, Germany

    • Jan Diekmann
    •  & Ugur Sahin
  4. La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, California 92037, USA

    • Stephen P. Schoenberger

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Contributions

U.S. is principal investigator, conceptualized the study and experimental strategy. S.K., M.V., N.vdR., M.D., J.D., F.V. and U.S. planned and analysed experiments. M.V. and N.vdR. performed experiments. S.K., M.V., M.D., S.P.S., C.H., Ö.T. and U.S. interpreted the data and wrote the manuscript. M.L., S.B., A.D.T. and J.C.C. processed next-generation sequencing data and identified mutations. M.V. and B.S. analysed murine MHC II binding predictions. S.B. analysed TCGA data and human MHC II binding predictions.

Corresponding author

Correspondence to Ugur Sahin.

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DOI

https://doi.org/10.1038/nature14426

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