Mutations are regarded as ideal targets for cancer immunotherapy. As neo-epitopes with strict lack of expression in any healthy tissue, they are expected to be safe. The systematic use of mutations for vaccine approaches, however, is hampered by the uniqueness of the repertoire of mutations (the mutanome) in every patient's tumor. We have recently proposed a personalized immunotherapy approach targeting the spectrum of individual mutations. Preclinically we could show in three independent murine tumor models that a considerable fraction of non-synonymous cancer mutations is immunogenic and that unexpectedly the immunogenic mutanome is pre-dominantly recognized by CD4+ T cells (the CD4+ immunome). Vaccination with such CD4+ immunogenic mutations confers strong antitumor activity. Encouraged by these findings we set up a process comprising mutation detection by exome sequencing, selection of vaccine targets by solely bioinformatical prioritization of mutated epitopes predicted to be abundantly expressed and good MHC class II binders and rapid production of synthetic mRNA vaccines encoding multiple of these mutated epitopes. We show that vaccination with such poly-neo-epitopic mRNA vaccines induces potent tumor control and complete rejection of established aggressively growing tumors in mice.
End of 2013 this approach has been translated from bench to bedside when a first in human clinical study started demonstrating the clinical feasibility of the approach (NCT02035956). This tailored immunotherapy approach may be regarded as a universally applicable blueprint for comprehensive exploitation of the huge neo-epitope target repertoire of cancers enabling the treatment of patients by targeting every patient's tumor with individual just in time produced vaccines.
Citation Format: Ugur Sahin. Targeting the mutanome for individualized cancer immunotherapy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr IA06.