Intravesical instillation therapy with bacillus Calmette‐Guérin for superficial bladder cancer: Study of the mechanism of bacillus Calmette‐Guérin immunotherapy

Abstract

Aim:In order to clarify the initial step of the mechanism by which bacillus Calmette-Guérin (BCG) exhibits antitumor activity via the immune response induced in the bladder submucosa after intravesical BCG therapy for human bladder cancer, various cytokines secreted in the urine after BCG instillation were measured. Methods: After transurethral resection of bladder cancer, a 6-week course of BCG instillation was performed. At the first and sixth weeks' dosings, spontaneously excreted urine was collected before and 4, 8, and 24 h after BCG instillation. The urinary cytokines were determined by Sandwich enzyme-linked immunosorbent assay using monoclonal antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF)-a, granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-1b, IL-8, interferon (IFN)-g, and IL-12. Results: After the BCG therapy, various cytokines, such as GM-CSF, TNF-a, G-CSF, IL-1b, IL-8, IFN-g, and IL-12 were secreted , comprising the immune response cascade. The mean urinary excretions of GM-CSF and TNF-a 4 h after the sixth week's instillation were significantly higher than the pre-instillation levels. There were no significant increases in the urinary IFN-g or IL-12 levels between 4 and 24 h after the sixth week's instillation. The TNF-a level 4 h after the sixth week's instillation had a strong tendency towards the absence of recurrence, with a mean follow-up of 54.1 months. The Kaplan-Meier curve showed the 2, 5, and 10-year recurrence-free survival rates were 72.4%, 65.8%, and 56.4%, respectively. Conclusions: We suggested that the urinary levels of TNF-a might be essential in antitumor activity after BCG therapy and might play an important role in the prevention of bladder tumor recurrence.

Dendritic cells in blood and urine samples from bladder cancer patients undergoing BCG immunotherapy

“…Superficial tumors are confined to the mucosa clear. Recently, some studies correlated the presence of leukocytes in the urine of patients with bladder cancer undergoing BCG therapy with a reduction of recurrence (10). DCs were found in the urine of bladder cancer patients, and it was speculated that variability in the percentage of urinary DCs may reflect changes in immunological activity at the tumor site (32).…”

“…A local inflamma-Summary tion, characterized by an influx of mononuclear cells into the bladder wall and by the secretion of pro-inflammatory cytokines into the urine, has been described in patients undergoing BCG instillations (7)(8)(9). Recently, a central role in the prevention bladder tumor recurrence has been suggested for granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF)-α, which are essential cytokines in the induction of dendritic cell (DC) response (10). In fact, both natural and adap-tative immunity seem to be involved in the local response to BCG therapy.…”

Efficacy of bacillus Calmette‐Guérin in the treatment of superficial bladder cancer: The impact of previous intravesical treatment

“…Although the anti-cancer mechanisms of BCG are not totally understood , they are definitely considered to involve immunological reactions. [17][18][19][20][21] It is also necessary to consider the possibility of tumor-side factors, including patient's condition, idea of attending doctor, etc. To confirm the result in this study, large scale randomized controlled trial is essential in the future.…”

Microbial-based therapy of cancer: Current progress and future prospects

“…63 Several cytokines have been reported to be increased in patients treated with BCG: Interleukin-2, 6, 8, 10, 12, TNF and INFα,γ. 64 TRAIL is capable of inducing apoptosis in neoplastic cells but not in normal cells 65 and it appears to be of pivotal importance in BCG-response. Neutrophils are its primary producers and its levels are increased in the urine of BCG-responders compared to BCG non-responders.…”