Immunotherapy of experimental bladder cancer with recombinant BCG expressing interferon-gamma.
One of the most potent immunotherapies presently used is the application of Bacillus Calmette Guérin (BCG) to prevent recurrences of superficial bladder cancer. Despite its successful use, nonresponders and certain side effects remain a major obstacle. Therefore, current studies aim at developing recombinant BCG (rBCG) strains to further improve the effectiveness of the therapy. In BCG-treated patients a strong local induction of Th1-like cytokines was observed. For this reason rBCG-strains secreting Th1-like cytokines might be potentially useful agents to improve this type of immunotherapy. Because we previously demonstrated the essential role of IFNgamma in BCG-induced antitumor responses, in this study a rBCG strain secreting murine IFNgamma (rBCG-IFNgamma) was generated and tested for its immunostimulatory capacity in several in vitro and in vivo test systems. In vitro rBCG-IFNgamma specifically up-regulated expression of MHC class I molecules on a murine bladder cancer cell line (MB49), compared to the rBCG control strain (transfected with an empty vector). In a murine model of experimental bladder cancer, intravesical instillation of rBCG-IFNgamma resulted in an enhanced recruitment of CD4+ T-cells into the bladder and further induced the local expression of IL-2 and IL-4 cytokines (mRNA) compared to control rBCG. With a low-dose treatment regimen for murine orthotopic bladder cancer, rBCG-IFNgamma significantly prolonged survival, whereas the therapeutic effect of wild-type control BCG did not reach statistical significance. We conclude that this recombinant BCG strain has enhanced immunostimulatory potential and might offer new opportunities in the treatment of bladder cancer.
Arnold
Judith
J
Research Center Borstel, Division of Immunotherapy, Borstel, Germany.
de Boer
Elizabeth C
EC
O'Donnell
Michael A
MA
Böhle
Andreas
A
Brandau
Sven
S
D000818:Animals; D001500:BCG Vaccine / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D004396:Coloring Agents / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000276:immunology* / Q000378:metabolism
D001500:BCG Vaccine; D004396:Coloring Agents; D007376:Interleukin-2; D012333:RNA, Messenger; D011994:Recombinant Proteins; D013778:Tetrazolium Salts; D013844:Thiazoles; D015847:Interleukin-4; D012313:RNA; D007371:Interferon-gamma; C022616:thiazolyl blue