Bladder Cancer Immunotherapy: BCG and Beyond

Department of Urology, University of Iowa, 375 Newton Road, 3204 MERF, Iowa City, IA 52242, USA.
Advances in Urology 06/2012; 2012(3):181987. DOI: 10.1155/2012/181987
Source: PubMed


Mycobacterium bovis bacillus Calmette-Guérin (BCG) has become the predominant conservative treatment for nonmuscle invasive bladder cancer. Its mechanism of action continues to be defined but has been shown to involve a T helper type 1 (Th1) immunomodulatory response. While BCG treatment is the current standard of care, a significant proportion of patients fails or do not tolerate treatment. Therefore, many efforts have been made to identify other intravesical and immunomodulating therapeutics to use alone or in conjunction with BCG. This paper reviews the progress of basic science and clinical experience with several immunotherapeutic agents including IFN-α, IL-2, IL-12, and IL-10.

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Available from: Michael A. O’Donnell, Nov 10, 2014
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    • "In the present case, the enlarged lymph nodes at bilateral neck level II areas turned out to be chronic granulomatous lymphadenopathy, which might be induced by either BCG lymphadenitis or mycobacterial infection. BCG irrigation after bladder cancer surgery is increasingly employed as a conservative treatment method [18]. BCG lymphadenitis was reported in some cases after BCG irrigation [19]. "
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    • "This is characterized by the appearance of different leukocytes and cytokines in the urine of BCG-treated patients. While the specific role that various cell types and cytokines play in urothelial carcinoma treatment is not completely clear, urinary Th1 cytokines (e.g., IFNγ, IL-2, and IL-12) have been associated with the BCG response, whereas high levels of Th2 cytokines (e.g., IL-10 and IL-6) correlate with BCG failure [9]–[16]. Overall, the ability of intravesical BCG to interact with the urothelium and stimulate broad, durable Th1- type immune responses is probably critical to its efficacy. "
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    ABSTRACT: Intravesical Bacillus Calmette-Guérin (BCG) has been shown to induce a specific immunologic response (i.e., activation of IL-2 and effector T-cells), while preclinical studies using ALT-803 (mutated IL-15 analogue combined with IL-15Rα-Fc fusion) have shown promising results by prolonging the agent's half-life and stimulating CD8+ T-cells. Based on these results, we hypothesized that the intravesical administration of ALT-803 along with BCG will generate an immunologic response leading to significant bladder tumor burden reduction. Using a well-established carcinogen induced rat non-muscle invasive bladder cancer (NMIBC) model, we studied the effects of intravesical ALT-803 with and without BCG. Rat tissues were evaluated to document treatment response. Intravesical ALT-803 was safe and well tolerated alone and in combination with BCG. As a single treatment agent, ALT-803 reduced tumor burden by 35% compared to control whereas BCG alone only reduced tumor burden by 15%. However, the combination of ALT-803 plus BCG reduced tumor burden by 46% compared to control. Immune monitoring suggested that the antitumor response was linked to the production and secretion of IL-1α, IL-1β and RANTES, which in turn, induced the proliferation and activation of NK cells. Lastly, tumoral responses of the combinational treatment were associated with 76% reduction in angiogenesis, which is significantly higher than when assessed with either agent alone. The enhanced therapeutic index seen with this duplet provides justification for the development of this regimen for future clinical trials.
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    • "The mechanism of action of intravesical BCG is incompletely characterized. However BCG-induced anti-tumor activity, depends on both, local and systemic immunological responses [20]. After initiating intravesical BCG instillation, immune stimulation generally peaks at 6 weeks. "
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