title: Combination immunotherapy and active-specific tumor cell vaccination augments anti-cancer immunity in a mouse model of gastric cancer.
abstract: BACKGROUND
  Active-specific immunotherapy used as an adjuvant therapeutic strategy is rather unexplored for cancers with poorly characterized tumor antigens like gastric cancer. The aim of this study was to augment a therapeutic immune response to a low immunogenic tumor cell line derived from a spontaneous gastric tumor of a CEA424-SV40 large T antigen (CEA424-SV40 TAg) transgenic mouse.
  
  
  METHODS
  Mice were treated with a lymphodepleting dose of cyclophosphamide prior to reconstitution with syngeneic spleen cells and vaccination with a whole tumor cell vaccine combined with GM-CSF (a treatment strategy abbreviated as LRAST). Anti-tumor activity to subcutaneous tumor challenge was examined in a prophylactic as well as a therapeutic setting and compared to corresponding controls.
  
  
  RESULTS
  LRAST enhances tumor-specific T cell responses and efficiently inhibits growth of subsequent transplanted tumor cells. In addition, LRAST tended to slow down growth of established tumors. The improved anti-tumor immune response was accompanied by a transient decrease in the frequency and absolute number of CD4⁺CD25⁺FoxP3⁺ T cells (Tregs).
  
  
  CONCLUSIONS
  Our data support the concept that whole tumor cell vaccination in a lymphodepleted and reconstituted host in combination with GM-CSF induces therapeutic tumor-specific T cells. However, the long-term efficacy of the treatment may be dampened by the recurrence of Tregs. Strategies to counteract suppressive immune mechanisms are required to further evaluate this therapeutic vaccination protocol.
authors.affiliation: Department of Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany. natasja.vandenengel@med.uni-muenchen.de
authors.forename: Natasja K
authors.initials: NK
authors.lastname: van den Engel
authors.forename: Dominik
authors.initials: D
authors.lastname: Rüttinger
authors.forename: Margareta
authors.initials: M
authors.lastname: Rusan
authors.forename: Robert
authors.initials: R
authors.lastname: Kammerer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Zimmermann
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: Hatz
authors.forename: Hauke
authors.initials: H
authors.lastname: Winter
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use; D007109:Immunity / Q000276:immunology*; D007167:Immunotherapy; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013997:Time Factors; D016896:Treatment Outcome; D014611:Vaccination
chemical_list: D019496:Cancer Vaccines; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D005620:Freund's Adjuvant