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

U Sahin, E Derhovanessian, M Miller, BP Kloke… - Nature, 2017 - nature.com
U Sahin, E Derhovanessian, M Miller, BP Kloke, P Simon, M Löwer, V Bukur, AD Tadmor…
Nature, 2017nature.com
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 …
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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