title: Antitumor effects of L-BLP25 antigen-specific tumor immunotherapy in a novel human MUC1 transgenic lung cancer mouse model.
abstract: BACKGROUND
  L-BLP25 antigen-specific cancer immunotherapeutic agent is currently in phase III clinical trials for non-small cell lung cancer. Using a novel human MUC1 transgenic (hMUC1.Tg) lung cancer mouse model, we evaluated effects of L-BLP25 combined with low-dose cyclophosphamide (CPA) pretreatment on Th1/Th2 cytokine production and antitumor activity.
  
  
  METHODS
  A chemically-induced lung tumor model was developed in hMUC1.Tg C57BL/6 mice by administering 10 weekly 0.75-mg/g doses of the chemical carcinogen urethane by intraperitoneal injection. Serum cytokines associated with Th1/Th2 polarization and inflammation were measured by multiplex cytokine assay during tumorigenesis. Antitumor activity of L-BLP25 (10 μg) with CPA (100 mg/kg) pretreatment was evaluated following either one or two eight-week cycles of treatment by preparing lung whole mounts and counting tumor foci, and assessing IFN-γ production by ELISpot assay.
  
  
  RESULTS
  During the carcinogenesis phase, no detectable Th1- or Th2-associated cytokine responses were observed, but levels of pro-inflammatory cytokines were increased with distinctive kinetics. A single cycle of L-BLP25 consisting of eight weekly doses was ineffective, whereas adding a second cycle given during tumor progression showed a significant reduction in the incidence of tumor foci. Administering two cycles of L-BLP25 induced Th1 cytokines IL-12, IL-2 and IFNγ at 24 h after the last dose, while Th2 and inflammatory cytokines were elevated to a lesser extent.
  
  
  CONCLUSIONS
  Urethane-induced lung tumors in hMUC1.Tg mice can be used as a model to assess the efficacy of the MUC1 antigen-specific cancer immunotherapeutic agent L-BLP25. The results indicate that the antitumor response to L-BLP25 requires at least two cycles and pre-treatment with CPA. In addition, monitoring pro-inflammatory serum cytokines may be useful as a biomarker of L-BLP25 response. Taken together, the preclinical lung tumor model can be utilized for determining effective combinations of L-BLP25 with chemotherapy and/or other immunotherapies.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Wurz
authors.forename: Audrey M
authors.initials: AM
authors.lastname: Gutierrez
authors.forename: Brittany E
authors.initials: BE
authors.lastname: Greenberg
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Vang
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Griffey
authors.forename: Chiao-Jung
authors.initials: CJ
authors.lastname: Kao
authors.forename: Michael
authors.initials: M
authors.lastname: Wolf
authors.forename: Michael W
authors.initials: MW
authors.lastname: DeGregorio
mesh_terms: D000236:Adenoma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D063646:Carcinogenesis / Q000473:pathology; D003520:Cyclophosphamide / Q000494:pharmacology / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007109:Immunity / Q000187:drug effects; D007167:Immunotherapy; D018836:Inflammation Mediators / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000276:immunology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018396:Mucin-1 / Q000276:immunology*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D014520:Urethane
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D016207:Cytokines; D018836:Inflammation Mediators; C518273:L-BLP25; D008562:Membrane Glycoproteins; D018396:Mucin-1; D014520:Urethane; D003520:Cyclophosphamide