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. 2017 Jul 13;547(7662):222-226.
doi: 10.1038/nature23003. Epub 2017 Jul 5.

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

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

Ugur Sahin et al. Nature. .

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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