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.

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