Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer
A partir de l'analyse du génome tumoral de patients atteints d'un mélanome (6 et 13 patients), ces études analysent la faisabilité, l'immunogénicité et l'efficacité, du point de vue du taux de réponse objective et de l'amélioration de la survie sans progression, de vaccins thérapeutiques personnalisés stimulant l’activité des lymphocytes T cytotoxiques CD8+ et CD4+ dirigée contre les cellules tumorales et les mutations spécifiques de chacun des patients
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.
Nature , résumé, 2016