Bladder Cancer Immunotherapy: BCG and Beyond

Abstract

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.

Figure 1

Suggested cascade of immune responses in bladder mucosa induced by intravesical BCG instillation. Attachment of BCG to urothelial cells including carcinoma cells triggers release of cytokines and chemokines from these cells, resulting in recruitment of various types of immune cells into the bladder wall. Activation of phagocytes and the new cytokine environment lead to the differentiation of naïve CD4⁺ T cells into TH1 and/or TH2 cells that direct immune responses toward cellular or humoral immunity, respectively. The therapeutic effect of BCG depends on a proper induction of TH1 immune responses. IL-10 inhibits TH1 immune responses, whereas IFN-γ inhibits TH2 immune responses. Blocking IL-10 or inducing IFN-γ can lead to a TH1-dominated immunity that is essential for BCG-mediated bladder cancer destruction.