title: A Therapeutic Her2/neu Vaccine Targeting Dendritic Cells Preferentially Inhibits the Growth of Low Her2/neu-Expressing Tumor in HLA-A2 Transgenic Mice.
abstract: OBJECTIVE
  E75, a peptide derived from the Her2/neu protein, is the most clinically advanced vaccine approach against breast cancer. In this study, we aimed to optimize the E75 vaccine using a delivery vector targeting dendritic cells, the B-subunit of Shiga toxin (STxB), and to assess the role of various parameters (Her2/neu expression, combination with trastuzumab) in the efficacy of this cancer vaccine in a relevant preclinical model.
  
  
  METHODS
  We compared the differential ability of the free E75 peptide or the STxB-E75 vaccine to elicit CD8(+) T cells, and the impact of the vaccine on murine HLA-A2 tumors expressing low or high levels of Her2/neu.
  
  
  RESULTS
  STxB-E75 synergized with granulocyte macrophage colony-stimulating factors and CpG and proved to be more efficient than the free E75 peptide in the induction of multifunctional and high-avidity E75-specific anti-CD8(+) T cells resulting in a potent tumor protection in HLA-A2 transgenic mice. High expression of HER2/neu inhibited the expression of HLA-class I molecules, leading to a poor recognition of human or murine tumors by E75-specific cytotoxic CD8(+) T cells. In line with these results, STxB-E75 preferentially inhibited the growth of HLA-A2 tumors expressing low levels of Her2/neu. Coadministration of anti-Her2/neu mAb potentiated this effect.
  
  
  CONCLUSIONS
  STxB-E75 vaccine is a potent candidate to be tested in patients with low Her2/neu-expressing tumors. It could also be indicated in patients expressing high levels of Her2/neu and low intratumoral T-cell infiltration to boost the recruitment of T cells-a key parameter in the efficacy of anti-Her2/neu mAb therapy. Clin Cancer Res; 22(16); 4133-44. ©2016 AACR.
authors.affiliation: INSERM U970, Université Paris Descartes, Sorbonne Paris-Cité, Paris, France. Equipe Labellisée Ligue Contre le Cancer, Paris, France.
authors.forename: Thi
authors.initials: T
authors.lastname: Tran
authors.affiliation: INSERM U970, Université Paris Descartes, Sorbonne Paris-Cité, Paris, France. Equipe Labellisée Ligue Contre le Cancer, Paris, France. Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Mariana O
authors.initials: MO
authors.lastname: Diniz
authors.affiliation: Institut Curie, PSL Research University, Chemical Biology of Membranes and Therapeutic Delivery Unit. INSERM, U 1143. CNRS, UMR 3666, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Dransart
authors.affiliation: Service d'Immunologie biologique, Hopital Européen Georges Pompidou-APHP, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Gey
authors.affiliation: INSERM U970, Université Paris Descartes, Sorbonne Paris-Cité, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Merillon
authors.affiliation: Inserm U-1014, Université Paris XI, Groupe Hospitalier Paul-Brousse, France.
authors.forename: Yu Chun
authors.initials: YC
authors.lastname: Lone
authors.affiliation: Immuno Target SAS, Paris, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Godefroy
authors.affiliation: Immuno Target SAS, Paris, France.
authors.forename: Craig
authors.initials: C
authors.lastname: Sibley
authors.affiliation: Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Luis Cs
authors.initials: LC
authors.lastname: Ferreira
authors.affiliation: Service d'Oncologie Médicale, Hopital Européen Georges Pompidou, Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Medioni
authors.affiliation: INSERM U970, Université Paris Descartes, Sorbonne Paris-Cité, Paris, France. Equipe Labellisée Ligue Contre le Cancer, Paris, France. Service d'Oncologie Médicale, Hopital Européen Georges Pompidou, Paris, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Oudard
authors.affiliation: Institut Curie, PSL Research University, Chemical Biology of Membranes and Therapeutic Delivery Unit. INSERM, U 1143. CNRS, UMR 3666, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
authors.forename: Ludger
authors.initials: L
authors.lastname: Johannes
authors.affiliation: INSERM U970, Université Paris Descartes, Sorbonne Paris-Cité, Paris, France. Equipe Labellisée Ligue Contre le Cancer, Paris, France. Service d'Immunologie biologique, Hopital Européen Georges Pompidou-APHP, Paris, France. eric.tartour@aphp.fr.
authors.forename: Eric
authors.initials: E
authors.lastname: Tartour
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015789:HLA-A2 Antigen / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D008546:Melanoma, Experimental; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D010446:Peptide Fragments / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human