Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer

  • Nature. 2017 Jul 13;547(7662):222-226. doi: 10.1038/nature23003.
Ugur Sahin  1  2  3 ,  Evelyna Derhovanessian  1 ,  Matthias Miller  1 ,  Björn-Philipp Kloke  1 ,  Petra Simon  1 ,  Martin Löwer  2 ,  Valesca Bukur  1  2 ,  Arbel D Tadmor  2 ,  Ulrich Luxemburger  1 ,  Barbara Schrörs  2 ,  Tana Omokoko  1 ,  Mathias Vormehr  1  3 ,  Christian Albrecht  2 ,  Anna Paruzynski  1 ,  Andreas N Kuhn  1 ,  Janina Buck  1 ,  Sandra Heesch  1 ,  Katharina H Schreeb  1 ,  Felicitas Müller  1 ,  Inga Ortseifer  1 ,  Isabel Vogler  1 ,  Eva Godehardt  1 ,  Sebastian Attig  2  3 ,  Richard Rae  2 ,  Andrea Breitkreuz  1 ,  Claudia Tolliver  1 ,  Martin Suchan  2 ,  Goran Martic  2 ,  Alexander Hohberger  3 ,  Patrick Sorn  2 ,  Jan Diekmann  1 ,  Janko Ciesla  4 ,  Olga Waksmann  4 ,  Alexandra-Kemmer Brück  1 ,  Meike Witt  1 ,  Martina Zillgen  1 ,  Andree Rothermel  2 ,  Barbara Kasemann  2 ,  David Langer  1 ,  Stefanie Bolte  1 ,  Mustafa Diken  1  2 ,  Sebastian Kreiter  1  2 ,  Romina Nemecek  5 ,  Christoffer Gebhardt  6  7 ,  Stephan Grabbe  3 ,  Christoph Höller  5 ,  Jochen Utikal  6  7 ,  Christoph Huber  1  2  3 ,  Carmen Loquai  3 ,  Özlem Türeci  8
Affiliations
  • 1. Biopharmaceutical New Technologies (BioNTech) Corporation, An der Goldgrube 12, 55131 Mainz, Germany.
  • 2. TRON - Translational Oncology at the University Medical Center of Johannes Gutenberg University gGmbH, Freiligrathstraße 12, 55131 Mainz, Germany.
  • 3. University Medical Center of the Johannes Gutenberg University, Langenbeckstraße 1, 55131 Mainz, Germany.
  • 4. EUFETS GmbH, Vollmersbachstraße 66, 55743 Idar-Oberstein, Germany.
  • 5. Medical University of Vienna, Spitalgasse 23, 1090 Vienna, Austria.
  • 6. German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
  • 7. University Medical Center Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68135 Mannheim, Germany.
  • 8. CI3 - Cluster for Individualized Immunointervention e.V, Hölderlinstraße 8, 55131 Mainz, Germany.
PMID: 28678784 DOI: 10.1038/nature23003
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 mutations. 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.