The mechanism of action of BCG therapy for bladder cancer—a current perspective

Subjects

Key Points

  • Despite nearly four decades of clinical experience with Bacillus Calmette–Guérin (BCG) for bladder cancer, the mechanism of its therapeutic effect is still under investigation

  • The requirements for effective BCG therapy include an intact immune system, live BCG, and close contact of BCG with bladder cancer cells

  • Important constituents of the cellular inflammatory response to BCG include CD4+ and CD8+ lymphocytes, natural killer cells, and granulocytes

  • Important elements of the humoral immune response to BCG include TRAIL (tumour necrosis factor-related apoptosis-inducing ligand), IL-2, IL-8, IL-18, IL-12, interferon (IFN)-γ, and tumour necrosis factor (TNF)

  • Bladder cancer cells and benign urothelial cells might have a role in the initial recognition and processing of BCG, leading to immune system recruitment

  • Future investigation will hopefully lead to the discovery of clinically useful predictors of response to BCG and development of recombinant BCG strains with improved efficacy and decreased toxicity

Abstract

Bacillus Calmette–Guérin (BCG) has been used to treat non-muscle-invasive bladder cancer for more than 30 years. It is one of the most successful biotherapies for cancer in use. Despite long clinical experience with BCG, the mechanism of its therapeutic effect is still under investigation. Available evidence suggests that urothelial cells (including bladder cancer cells themselves) and cells of the immune system both have crucial roles in the therapeutic antitumour effect of BCG. The possible involvement of bladder cancer cells includes attachment and internalization of BCG, secretion of cytokines and chemokines, and presentation of BCG and/or cancer cell antigens to cells of the immune system. Immune system cell subsets that have potential roles in BCG therapy include CD4+ and CD8+ lymphocytes, natural killer cells, granulocytes, macrophages, and dendritic cells. Bladder cancer cells are killed through direct cytotoxicity by these cells, by secretion of soluble factors such as TRAIL (tumour necrosis factor-related apoptosis-inducing ligand), and, to some degree, by the direct action of BCG. Several gaps still exist in our knowledge that should be addressed in future efforts to understand this biotherapy of cancer.

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Figure 1: Tentative model of the mechanism of action of BCG in bladder cancer.

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G.R.-S. researched the data for the article, provided a substantial contribution to discussion of the content, and wrote the article. M.S.G. and B.H.B. contributed equally to review and/or editing of the manuscript before submission.

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Correspondence to Gil Redelman-Sidi.

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Redelman-Sidi, G., Glickman, M. & Bochner, B. The mechanism of action of BCG therapy for bladder cancer—a current perspective. Nat Rev Urol 11, 153–162 (2014). https://doi.org/10.1038/nrurol.2014.15

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