Personalized RNA Mutanome Vaccines Mobilize Poly-specific Therapeutic Immunity Against Cancer

Nature  ·  2017  ·  Impact 10

Ugur Sahin; Evelyna Derhovanessian; Matthias Miller; Björn-Philipp Kloke; Petra Simon; Martin Löwer; Valesca Bukur; Arbel D Tadmor; Ulrich Luxemburger; Barbara Schrörs; Tana Omokoko; Mathias Vormehr; Christian Albrecht; Anna Paruzynski; Andreas N Kuhn; Janina Buck; Sandra Heesch; Katharina H Schreeb; Felicitas Müller; Inga Ortseifer; Isabel Vogler; Eva Godehardt; Sebastian Attig; Richard Rae; Andrea Breitkreuz; Claudia Tolliver; Martin Suchan; Goran Martic; Alexander Hohberger; Patrick Sorn; Jan Diekmann; Janko Ciesla; Olga Waksmann; Alexandra-Kemmer Brück; Meike Witt; Martina Zillgen; Andree Rothermel; Barbara Kasemann; David Langer; Stefanie Bolte; Mustafa Diken; Sebastian Kreiter; Romina Nemecek; Christoffer Gebhardt; Stephan Grabbe; Christoph Höller; Jochen Utikal; Christoph Huber; Carmen Loquai; Özlem Türeci;

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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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