title: CpG therapy is superior to BCG in an orthotopic bladder cancer model and generates CD4+ T-cell immunity.
abstract: Bacillus Calmette Guérin (BCG) immunotherapy has been successful in extending tumor remission in bladder cancer, the fifth most common cancer in men. However, relapses are frequent and some patients develop resistance to BCG. CpGs were previously demonstrated to be effective in the murine MB49 model. In this paper, we modeled a more aggressive orthotopic bladder cancer than previously studied. Moreover, we compared standard BCG immunotherapy side-by-side with the Toll-like receptor-9 agonist CpG. MB49 tumor-bearing mice were treated with BCG or CpG and survival as well as tumor progression were observed over time. Urine, blood, and tumors were collected and analyzed. Mice were rechallenged and evaluated for tumor-specific immunity. In this study, CpGs induced a complete response of large aggressive orthotopic MB49 bladder tumors, resulting in tumor-specific systemic immunity. Further, data indicated that this potent antitumor effect required T cells. A comparison of CpGs and BCG in both a highly and less aggressive orthotopic tumor model, and in a subcutaneous tumor model, demonstrated that CpGs were superior to BCG. In the orthotopic model, BCG induced a local cytokine storm during treatment initiation whereas CpG affected a more refined cytokine pattern over time. Increased levels of cytokines in serum correlated with enhanced survival in the subcutaneous model. Further, immune cell depletion studies demonstrated that CpG-induced protective immunity was CD4+ T-cell dependent. Taken together, our data suggest that CpGs are superior to BCG for bladder cancer immunotherapy. Thus, this potent new drug may be an attractive therapeutic alternative and should be evaluated in bladder cancer patients.
authors.affiliation: Division of Clinical Immunology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Mangsbo
authors.forename: Christina
authors.initials: C
authors.lastname: Ninalga
authors.forename: Magnus
authors.initials: M
authors.lastname: Essand
authors.forename: Angelica
authors.initials: A
authors.lastname: Loskog
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Tötterman
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001500:BCG Vaccine / Q000494:pharmacology / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000652:urine; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology / Q000627:therapeutic use*; D040521:Subcutaneous Tissue / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology
chemical_list: D000276:Adjuvants, Immunologic; D000906:Antibodies; D001500:BCG Vaccine; C408982:CPG-oligonucleotide; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D009838:Oligodeoxyribonucleotides