CpG oligonucleotide therapy cures subcutaneous and orthotopic tumors and evokes protective immunity in murine bladder cancer.
Bacillus Calmette-Guerin (BCG) instillation is standard immunotherapy for superficial bladder carcinoma. However, many patients become refractory to BCG, giving impetus to the development of alternative therapies. CpG oligodeoxynucleotide (ODN) therapy has been shown to promote T(H)1-oriented antitumor responses in various tumor models. To investigate its therapeutic effect in bladder cancer, we used different CpG ODNs to treat C57BL/6 mice bearing the subcutaneous murine bladder tumor MB49. CpG type B ODN 1668 was superior at inhibiting tumor growth, leading to complete regression of large tumors. More importantly, CpG ODN 1668 also regressed orthotopically growing MB49 tumors for the first time. Rechallenge of CpG ODN-cured mice with MB49 showed that a majority of the mice were protected long term, demonstrating that CpG ODN therapy evokes a memory response. Adenoviral vectors (Ad) encoding CD40L, tumor necrosis factor-related activation-induced cytokine, lymphotactin, interleukin (IL) 2, and IL-15 were also investigated. AdCD40L and AdIL-15 transduction could abolish MB49 tumorigenicity, and these vectors were combined with CpG ODN 1668 to investigate any enhanced effects. No such effects were seen. All groups of mice treated with CpG ODNs, alone or in combination with adenoviral vector, exhibited increased serum concentrations of IL-12, indicative of a T(H)1 response. Our results show that CpG ODN therapy cures established subcutaneous and orthotopic bladder cancer via a T(H)1-mediated response and provides long-lasting protective immunity.
Ninalga
Christina
C
Rudbeck Laboratory, Clinical Immunology Division, Uppsala University, 751 85 Uppsala, Sweden.
Loskog
Angelica
A
Klevenfeldt
Magdalena
M
Essand
Magnus
M
Tötterman
Thomas H
TH
D000256:Adenoviridae / Q000235:genetics; D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000283:Administration, Intravesical; D000818:Animals; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology; D002295:Carcinoma, Transitional Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002460:Cell Line; D045744:Cell Line, Tumor; D019744:Chemokines, C / Q000235:genetics / Q000276:immunology; D004247:DNA / Q000627:therapeutic use; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000097:blood; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000627:therapeutic use*; D015996:Survival Rate; D014162:Transfection; D001749:Urinary Bladder Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D019744:Chemokines, C; C423449:CpG ODN 1826; D019409:Interleukin-15; D009838:Oligodeoxyribonucleotides; C486249:Xcl1 protein, mouse; D023201:CD40 Ligand; D018664:Interleukin-12; D004247:DNA