Abstract

T cells directed against mutant neo-epitopes drive cancer immunity. However, spontaneous immune recognition of mutations is inefficient. We recently introduced the concept of individualized mutanome vaccines and implemented an RNA-based poly-neo-epitope approach to mobilize immunity against a spectrum of cancer mutations1,2. Here we report the first-in-human application of this concept in melanoma. We set up a process comprising comprehensive identification of individual mutations, computational prediction of neo-epitopes, and design and manufacturing of a vaccine unique for each patient. All patients developed T cell responses against multiple vaccine neo-epitopes at up to high single-digit percentages. Vaccine-induced T cell infiltration and neo-epitope-specific killing of autologous tumour cells were shown in post-vaccination resected metastases from two patients. The cumulative rate of metastatic events was highly significantly reduced after the start of vaccination, resulting in a sustained progression-free survival. Two of the five patients with metastatic disease experienced vaccine-related objective responses. One of these patients had a late relapse owing to outgrowth of β2-microglobulin-deficient melanoma cells as an acquired resistance mechanism. A third patient developed a complete response to vaccination in combination with PD-1 blockade therapy. Our study demonstrates that individual mutations can be exploited, thereby opening a path to personalized immunotherapy for patients with cancer.

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Acknowledgements

We thank J. de Graaf, I. Eichelbrönner, L. Leppin, L. Giese and S. Vogler, D. Becker, M. Dorner, J. Grützner, M. Hossainzadeh, A. Selmi, S. Wessel, C. Ecker, M. Lochschmitt, B. Schmitz, C. Anft, N. Bidmon, H. Schröder, D. Barea Roldán, C. Walter, S. Wöll, C. Rohde, O. Renz, F. Bayer, C. Kröner, B. Otte, T. Stricker, M. Drude S. Petri, M. Mechler, L. Hebich, B. Steege, A. Oelbermann, J. Schwarz, C. Britten, J. C. Castle and B. Pless for technical support, project management and advice. We thank A. Tüttenberg for support with a figure. We thank I. Mellman, L. Delamarre and G. Fine for critical reading of the manuscript. We thank K. Sahin for her advice. The study was supported by the CI3 cluster program of the Federal Ministry of Education and Research (BMBF).

Author information

Author notes

    • Carmen Loquai
    •  & Özlem Türeci

    These authors contributed equally to this work.

Affiliations

  1. Biopharmaceutical New Technologies (BioNTech) Corporation, An der Goldgrube 12, 55131 Mainz, Germany

    • Ugur Sahin
    • , Evelyna Derhovanessian
    • , Matthias Miller
    • , Björn-Philipp Kloke
    • , Petra Simon
    • , Valesca Bukur
    • , Ulrich Luxemburger
    • , Tana Omokoko
    • , Mathias Vormehr
    • , Anna Paruzynski
    • , Andreas N. Kuhn
    • , Janina Buck
    • , Sandra Heesch
    • , Katharina H. Schreeb
    • , Felicitas Müller
    • , Inga Ortseifer
    • , Isabel Vogler
    • , Eva Godehardt
    • , Andrea Breitkreuz
    • , Claudia Tolliver
    • , Jan Diekmann
    • , Alexandra-Kemmer Brück
    • , Meike Witt
    • , Martina Zillgen
    • , David Langer
    • , Stefanie Bolte
    • , Mustafa Diken
    • , Sebastian Kreiter
    •  & Christoph Huber
  2. TRON – Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH, Freiligrathstraße 12, 55131 Mainz, Germany

    • Ugur Sahin
    • , Martin Löwer
    • , Valesca Bukur
    • , Arbel D. Tadmor
    • , Barbara Schrörs
    • , Christian Albrecht
    • , Sebastian Attig
    • , Richard Rae
    • , Martin Suchan
    • , Goran Martic
    • , Patrick Sorn
    • , Andree Rothermel
    • , Barbara Kasemann
    • , Mustafa Diken
    • , Sebastian Kreiter
    •  & Christoph Huber
  3. University Medical Center of the Johannes Gutenberg University, Langenbeckstraße 1, 55131 Mainz, Germany

    • Ugur Sahin
    • , Mathias Vormehr
    • , Sebastian Attig
    • , Alexander Hohberger
    • , Stephan Grabbe
    • , Christoph Huber
    •  & Carmen Loquai
  4. EUFETS GmbH, Vollmersbachstraße 66, 55743 Idar-Oberstein, Germany

    • Janko Ciesla
    •  & Olga Waksmann
  5. Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria

    • Romina Nemecek
    •  & Christoph Höller
  6. German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany

    • Christoffer Gebhardt
    •  & Jochen Utikal
  7. University Medical Center Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68135 Mannheim, Germany

    • Christoffer Gebhardt
    •  & Jochen Utikal
  8. CI3 - Cluster for Individualized Immunointervention e.V, Hölderlinstraße 8, 55131 Mainz, Germany

    • Özlem Türeci

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Contributions

U.S. conceptualized the work and strategy. E.D., Pe.Si., T.O., I.O., I.V., S.A., A.R. and B.K. planned and analysed experiments. E.G., R.R., A.B., C.T. and A.H. did experiments. M.L., V.B., A.D.T., B.S., C.A., A.P. and Pa.So. performed and analysed NGS runs. A.N.K., J.B. and J.C. manufactured the RNA vaccines, O.W., M.W. and M.Z. performed quality assurance. M.M., B.K., S.H., K.H.S., F.M., A.K.-B., D.L. and S.B. managed sample logistics. R.N., C.G., S.G., C.H., J.U. are clinical investigators. C.L. is the principal clinical investigator. U.L., J.D., M.D. and S.K. supported clinical grade assays. U.S., ÖT supported by E.D., M.V., Pe.Si., M.L, M.M., B.S. interpreted data and wrote the manuscript. All authors supported the revision of the manuscript.

Competing interests

Some of the authors are employees at BioNTech AG (Mainz, Germany) as mentioned in the affiliations. U.S. is stock owner of BioNTech AG (Mainz, Germany). U.S., M.L., B.S., M.V., A.N.K., M.D., A.T., Ö.T. and S.K. are inventors on patents and patent applications, which cover parts of this article.

Corresponding author

Correspondence to Ugur Sahin.

Reviewer Information Nature thanks C. Melief and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    This table lists the neo-epitope vaccine sequence for patient P04.

  2. 2.

    Supplementary Table 2

    This table summarizes all identified neo-epitopes across patients.

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