title: Mutant MHC class II epitopes drive therapeutic immune responses to cancer.
abstract: Tumour-specific mutations are ideal targets for cancer immunotherapy as they lack expression in healthy tissues and can potentially be recognized as neo-antigens by the mature T-cell repertoire. Their systematic targeting by vaccine approaches, however, has been hampered by the fact that every patient's tumour possesses a unique set of mutations ('the mutanome') that must first be identified. Recently, we proposed a personalized immunotherapy approach to target the full spectrum of a patient's individual tumour-specific mutations. Here we show in three independent murine tumour models that a considerable fraction of non-synonymous cancer mutations is immunogenic and that, unexpectedly, the majority of the immunogenic mutanome is recognized by CD4(+) T cells. Vaccination with such CD4(+) immunogenic mutations confers strong antitumour activity. Encouraged by these findings, we established a process by which mutations identified by exome sequencing could be selected as vaccine targets solely through bioinformatic prioritization on the basis of their expression levels and major histocompatibility complex (MHC) class II-binding capacity for rapid production as synthetic poly-neo-epitope messenger RNA vaccines. We show that vaccination with such polytope mRNA vaccines induces potent tumour control and complete rejection of established aggressively growing tumours in mice. Moreover, we demonstrate that CD4(+) T cell neo-epitope vaccination reshapes the tumour microenvironment and induces cytotoxic T lymphocyte responses against an independent immunodominant antigen in mice, indicating orchestration of antigen spread. Finally, we demonstrate an abundance of mutations predicted to bind to MHC class II in human cancers as well by employing the same predictive algorithm on corresponding human cancer types. Thus, the tailored immunotherapy approach introduced here may be regarded as a universally applicable blueprint for comprehensive exploitation of the substantial neo-epitope target repertoire of cancers, enabling the effective targeting of every patient's tumour with vaccines produced 'just in time'.
authors.affiliation: TRON - Translational Oncology at the University Medical Center of Johannes Gutenberg University, Freiligrathstrasse 12, 55131 Mainz, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kreiter
authors.affiliation: Research Center for Immunotherapy (FZI), Langenbeckstrasse 1, Building 708, 55131 Mainz, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Vormehr
authors.affiliation: Research Center for Immunotherapy (FZI), Langenbeckstrasse 1, Building 708, 55131 Mainz, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: van de Roemer
authors.affiliation: TRON - Translational Oncology at the University Medical Center of Johannes Gutenberg University, Freiligrathstrasse 12, 55131 Mainz, Germany.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Diken
authors.affiliation: TRON - Translational Oncology at the University Medical Center of Johannes Gutenberg University, Freiligrathstrasse 12, 55131 Mainz, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Löwer
authors.affiliation: 1] TRON - Translational Oncology at the University Medical Center of Johannes Gutenberg University, Freiligrathstrasse 12, 55131 Mainz, Germany [2] Biopharmaceutical New Technologies (BioNTech) Corporation, An der Goldgrube 12, 55131 Mainz, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Diekmann
authors.affiliation: TRON - Translational Oncology at the University Medical Center of Johannes Gutenberg University, Freiligrathstrasse 12, 55131 Mainz, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Boegel
authors.affiliation: TRON - Translational Oncology at the University Medical Center of Johannes Gutenberg University, Freiligrathstrasse 12, 55131 Mainz, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Schrörs
authors.affiliation: TRON - Translational Oncology at the University Medical Center of Johannes Gutenberg University, Freiligrathstrasse 12, 55131 Mainz, Germany.
authors.forename: Fulvia
authors.initials: F
authors.lastname: Vascotto
authors.affiliation: TRON - Translational Oncology at the University Medical Center of Johannes Gutenberg University, Freiligrathstrasse 12, 55131 Mainz, Germany.
authors.forename: John C
authors.initials: JC
authors.lastname: Castle
authors.affiliation: TRON - Translational Oncology at the University Medical Center of Johannes Gutenberg University, Freiligrathstrasse 12, 55131 Mainz, Germany.
authors.forename: Arbel D
authors.initials: AD
authors.lastname: Tadmor
authors.affiliation: La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, California 92037, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Schoenberger
authors.affiliation: Research Center for Immunotherapy (FZI), Langenbeckstrasse 1, Building 708, 55131 Mainz, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Huber
authors.affiliation: TRON - Translational Oncology at the University Medical Center of Johannes Gutenberg University, Freiligrathstrasse 12, 55131 Mainz, Germany.
authors.forename: Özlem
authors.initials: Ö
authors.lastname: Türeci
authors.affiliation: 1] TRON - Translational Oncology at the University Medical Center of Johannes Gutenberg University, Freiligrathstrasse 12, 55131 Mainz, Germany [2] Research Center for Immunotherapy (FZI), Langenbeckstrasse 1, Building 708, 55131 Mainz, Germany [3] Biopharmaceutical New Technologies (BioNTech) Corporation, An der Goldgrube 12, 55131 Mainz, Germany.
authors.forename: Ugur
authors.initials: U
authors.lastname: Sahin
mesh_terms: D000465:Algorithms; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology; D003198:Computer Simulation; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology; D059472:Exome / Q000235:genetics; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D009154:Mutation / Q000235:genetics*; D057285:Precision Medicine / Q000379:methods; D017422:Sequence Analysis, DNA; D016019:Survival Analysis
chemical_list: D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II