title: mRNA-based vaccines synergize with radiation therapy to eradicate established tumors.
abstract: BACKGROUND
  The eradication of large, established tumors by active immunotherapy is a major challenge because of the numerous cancer evasion mechanisms that exist. This study aimed to establish a novel combination therapy consisting of messenger RNA (mRNA)-based cancer vaccines and radiation, which would facilitate the effective treatment of established tumors with aggressive growth kinetics.
  
  
  METHODS
  The combination of a tumor-specific mRNA-based vaccination with radiation was tested in two syngeneic tumor models, a highly immunogenic E.G7-OVA and a low immunogenic Lewis lung cancer (LLC). The molecular mechanism induced by the combination therapy was evaluated via gene expression arrays as well as flow cytometry analyses of tumor infiltrating cells.
  
  
  RESULTS
  In both tumor models we demonstrated that a combination of mRNA-based immunotherapy with radiation results in a strong synergistic anti-tumor effect. This was manifested as either complete tumor eradication or delay in tumor growth. Gene expression analysis of mouse tumors revealed a variety of substantial changes at the tumor site following radiation. Genes associated with antigen presentation, infiltration of immune cells, adhesion, and activation of the innate immune system were upregulated. A combination of radiation and immunotherapy induced significant downregulation of tumor associated factors and upregulation of tumor suppressors. Moreover, combination therapy significantly increased CD4+, CD8+ and NKT cell infiltration of mouse tumors.
  
  
  CONCLUSIONS
  Our data provide a scientific rationale for combining immunotherapy with radiation and provide a basis for the development of more potent anti-cancer therapies.
authors.affiliation: CureVac GmbH, CureVac GmbH, Paul-Ehrlich-Str, 15, Tübingen 72076, Germany. mf@curevac.com.
authors.forename: Mariola
authors.initials: M
authors.lastname: Fotin-Mleczek
authors.forename: Kai
authors.initials: K
authors.lastname: Zanzinger
authors.forename: Regina
authors.initials: R
authors.lastname: Heidenreich
authors.forename: Christina
authors.initials: C
authors.lastname: Lorenz
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Kowalczyk
authors.forename: Karl-Josef
authors.initials: KJ
authors.lastname: Kallen
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Huber
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D018827:Carcinoma, Lewis Lung / Q000276:immunology*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000276:immunology*; D011878:Radiotherapy / Q000379:methods*
chemical_list: D019496:Cancer Vaccines; D012333:RNA, Messenger