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Nature ; 547(7662): 222-226, 2017 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-28678784

RESUMO

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 ß2-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.


Assuntos
Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Melanoma/imunologia , Melanoma/terapia , Mutação/genética , Medicina de Precisão/métodos , RNA/genética , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/imunologia , Antígenos CD8/imunologia , Vacinas Anticâncer/uso terapêutico , Epitopos/genética , Epitopos/imunologia , Humanos , Imunoterapia/métodos , Melanoma/genética , Metástase Neoplásica , Recidiva Local de Neoplasia/prevenção & controle , Nivolumabe , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/imunologia , Vacinação , Microglobulina beta-2/deficiência
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