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
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.
Subscribe to Journal
Get full journal access for 1 year
only $17.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Coley, W. B. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin. Orthop. Relat. Res. 262, 3–11 (1991).
Coley, W. B. The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proc. R. Soc. Med. 3, 1–48 (1910).
Sharma, P., Old, L. J. & Allison, J. P. Immunotherapeutic strategies for high-risk bladder cancer. Semin. Oncol. 34, 165–172 (2007).
Pearl, R. On the pathological relations between cancer and tuberculosis. Exp. Biol. Med. (Maywood) 26, 73–75 (1928).
Old, L. J., Clarke, D. A. & Benacerraf, B. Effect of Bacillus Calmette-Guerin infection on transplanted tumours in the mouse. Nature 184 (Suppl. 5), 291–292 (1959).
Carswell, E. A. et al. An endotoxin-induced serum factor that causes necrosis of tumors. Proc. Natl Acad. Sci. USA 72, 3666–3670 (1975).
Mathé, G. et al. Active immunotherapy for acute lymphoblastic leukaemia. Lancet 1, 697–699 (1969).
Morton, D. L. et al. BCG immunotherapy of malignant melanoma: summary of a seven-year experience. Ann. Surg. 180, 635–643 (1974).
Morales, A., Eidinger, D. & Bruce, A. W. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol. 116, 180–183 (1976).
Hall, M. C. et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J. Urol. 178, 2314–2330 (2007).
Babjuk, M. et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder, the 2011 update. Eur. Urol. 59, 997–1008 (2011).
Han, R. F. & Pan, J. G. Can intravesical bacillus Calmette-Guerin reduce recurrence in patients with superficial bladder cancer? A meta-analysis of randomized trials. Urology 67, 1216–1223 (2006).
Shelley, M. D. et al. A systematic review of intravesical bacillus Calmette-Guerin plus transurethral resection vs transurethral resection alone in Ta and T1 bladder cancer. BJU Int. 88, 209–216 (2001).
Sylvester, R. J., van der Meijden, A. P. & Lamm, D. L. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J. Urol. 168, 1964–1970 (2002).
Shang, P. F. et al. Intravesical Bacillus Calmette-Guerin versus epirubicin for Ta and T1 bladder cancer. Cochrane Database of Systematic Reviews, Art. No.: CD006885. http://dx.doi.org/10.1002/14651858.CD006885.pub2.
Shelley, M. D. et al. Intravesical bacillus Calmette-Guérin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials. BJU Int. 93, 485–490 (2004).
Zbar, B. & Rapp, H. J. Immunotherapy of guinea pig cancer with BCG. Cancer 34 (Suppl.), 1532–1540 (1974).
Morton, D., Eilber, F. R., Malmgren, R. A. & Wood, W. C. Immunological factors which influence response to immunotherapy in malignant melanoma. Surgery 68, 158–163 (1970).
Zbar, B. & Tanaka, T. Immunotherapy of cancer: regression of tumors after intralesional injection of living Mycobacterium bovis. Science 172, 271–273 (1971).
Kelley, D. R. et al. Intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer: effect of bacillus Calmette-Guerin viability on treatment results. J. Urol. 134, 48–53 (1985).
Biot, C. et al. Preexisting BCG-specific T cells improve intravesical immunotherapy for bladder cancer. Sci. Transl. Med. 4, 137ra72 (2012).
Zbar, B., Bernstein, I. D., Bartlett, G. L., Hanna, M. G. Jr & Rapp, H. J. Immunotherapy of cancer: regression of intradermal tumors and prevention of growth of lymph node metastases after intralesional injection of living Mycobacterium bovis. J. Natl Cancer Inst. 49, 119–130 (1972).
Latchamsetty, K. C. & Porter, C. R. Treatment of upper tract urothelial carcinoma: a review of surgical and adjuvant therapy. Rev. Urol. 8, 61–70 (2006).
Palou, J. et al. ICUD-EAU International Consultation on Bladder Cancer 2012: urothelial carcinoma of the prostate. Eur. Urol. 63, 81–87 (2013).
De Boer, E. C. et al. Presence of activated lymphocytes in the urine of patients with superficial bladder cancer after intravesical immunotherapy with bacillus Calmette-Guerin. Cancer Immunol. Immunother. 33, 411–416 (1991).
Bohle, A., Gerdes, J., Ulmer, A. J., Hofstetter, A. G. & Flad, H. D. Effects of local bacillus Calmette-Guerin therapy in patients with bladder carcinoma on immunocompetent cells of the bladder wall. J. Urol. 144, 53–58 (1990).
De Boer, E. C. et al. Induction of urinary interleukin-1 (IL-1), IL-2, IL-6, and tumour necrosis factor during intravesical immunotherapy with bacillus Calmette-Guerin in superficial bladder cancer. Cancer Immunol. Immunother. 34, 306–312 (1992).
de Boer, E. C. et al. Role of interleukin-8 in onset of the immune response in intravesical BCG therapy for superficial bladder cancer. Urol. Res. 25, 31–34 (1997).
Alexandroff, A., Jackson, A., Skibinska, A. & James, K. Production of IL-5, a classical T(H)2 cytokine, following bacillus Calmette guerin immunotherapy of bladder cancer. Int. J. Oncol. 9, 179–182 (1996).
O'Donnell, M. A. et al. Role of IL-12 in the induction and potentiation of IFN-gamma in response to bacillus Calmette-Guerin. J. Immunol. 163, 4246–4252 (1999).
Jackson, A. M. et al. Changes in urinary cytokines and soluble intercellular adhesion molecule-1 (ICAM-1) in bladder cancer patients after bacillus Calmette-Guerin (BCG) immunotherapy. Clin. Exp. Immunol. 99, 369–375 (1995).
Eto, M. et al. Importance of urinary interleukin-18 in intravesical immunotherapy with bacillus calmette-guerin for superficial bladder tumors. Urol. Int. 75, 114–118 (2005).
Luo, Y., Chen, X. & O'Donnell, M. A. Mycobacterium bovis bacillus Calmette-Guerin (BCG) induces human CC- and CXC-chemokines in vitro and in vivo. Clin. Exp. Immunol. 147, 370–378 (2007).
Lage, J. M., Bauer, W. C., Kelley, D. R., Ratliff, T. L. & Catalona, W. J. Histological parameters and pitfalls in the interpretation of bladder biopsies in bacillus Calmette-Guerin treatment of superficial bladder cancer. J. Urol. 135, 916–919 (1986).
Ratliff, T. L., Gillen, D. & Catalona, W. J. Requirement of a thymus dependent immune response for BCG-mediated antitumor activity. J. Urol. 137, 155–158 (1987).
Boccafoschi, C. et al. Immunophenotypic characterization of the bladder mucosa infiltrating lymphocytes after intravesical BCG treatment for superficial bladder carcinoma. Eur. Urol. 21, 304–308 (1992).
Ratliff, T. L., Ritchey, J. K., Yuan, J. J., Andriole, G. L. & Catalona, W. J. T-cell subsets required for intravesical BCG immunotherapy for bladder cancer. J. Urol. 150, 1018–1023 (1993).
Ratliff, T. L., Shapiro, A. & Catalona, W. J. Inhibition of murine bladder tumor growth by bacille Calmette-Guerin: lack of a role of natural killer cells. Clin. Immunol. Immunopathol. 41, 108–115 (1986).
Shapiro, A., Ratliff, T. L., Oakley, D. M. & Catalona, W. J. Reduction of bladder tumor growth in mice treated with intravesical Bacillus Calmette-Guerin and its correlation with Bacillus Calmette-Guerin viability and natural killer cell activity. Cancer Res. 43, 1611–1615 (1983).
Sonoda, T., Sugimura, K., Ikemoto, S., Kawashima, H. & Nakatani, T. Significance of target cell infection and natural killer cells in the anti-tumor effects of bacillus Calmette-Guerin in murine bladder cancer. Oncol. Rep. 17, 1469–1474 (2007).
Brandau, S. et al. NK cells are essential for effective BCG immunotherapy. Int. J. Cancer 92, 697–702 (2001).
Brandau, S. & Bohle, A. Activation of natural killer cells by Bacillus Calmette-Guerin. Eur. Urol. 39, 518–524 (2001).
Suttmann, H. et al. Mechanisms of bacillus Calmette-Guerin mediated natural killer cell activation. J. Urol. 172, 1490–1495 (2004).
Brandau, S. et al. Perforin-mediated lysis of tumor cells by Mycobacterium bovis Bacillus Calmette-Guerin-activated killer cells. Clin. Cancer Res. 6, 3729–3738 (2000).
Siracusano, S. et al. The role of granulocytes following intravesical BCG prophylaxis. Eur. Urol. 51, 1589–1597 (2007).
Suttmann, H. et al. Neutrophil granulocytes are required for effective Bacillus Calmette-Guerin immunotherapy of bladder cancer and orchestrate local immune responses. Cancer Res. 66, 8250–8257 (2006).
Wang, S. & El-Deiry, W. S. TRAIL and apoptosis induction by TNF-family death receptors. Oncogene 22, 8628–8633 (2003).
Prescott, S., James, K., Hargreave, T. B., Chisholm, G. D. & Smyth, J. F. Intravesical Evans strain BCG therapy: quantitative immunohistochemical analysis of the immune response within the bladder wall. J. Urol. 147, 1636–1642 (1992).
Pryor, K. et al. Bacillus Calmette-Guerin (BCG) enhances monocyte- and lymphocyte-mediated bladder tumour cell killing. Br. J. Cancer 71, 801–807 (1995).
Yamada, H., Matsumoto, S., Matsumoto, T., Yamada, T. & Yamashita, U. Enhancing effect of an inhibitor of nitric oxide synthesis on bacillus Calmette-Guerin-induced macrophage cytotoxicity against murine bladder cancer cell line MBT-2 in vitro. Jpn J. Cancer Res. 91, 534–542 (2000).
Yamada, H., Matsumoto, S., Matsumoto, T., Yamada, T. & Yamashita, U. Murine IL-2 secreting recombinant Bacillus Calmette-Guerin augments macrophage-mediated cytotoxicity against murine bladder cancer MBT-2. J. Urol. 164, 526–531 (2000).
Luo, Y., Yamada, H., Evanoff, D. P. & Chen, X. Role of Th1-stimulating cytokines in bacillus Calmette-Guerin (BCG)-induced macrophage cytotoxicity against mouse bladder cancer MBT-2 cells. Clin. Exp. Immunol. 146, 181–188 (2006).
Luo, Y., Han, R., Evanoff, D. P. & Chen, X. Interleukin-10 inhibits Mycobacterium bovis bacillus Calmette-Guerin (BCG)-induced macrophage cytotoxicity against bladder cancer cells. Clin. Exp. Immunol. 160, 359–368 (2010).
Shintani, Y. et al. Intravesical instillation therapy with bacillus Calmette-Guerin for superficial bladder cancer: study of the mechanism of bacillus Calmette-Guerin immunotherapy. Int. J. Urol. 14, 140–146 (2007).
Atkinson, S., Valadas, E., Smith, S. M., Lukey, P. T. & Dockrell, H. M. Monocyte-derived macrophage cytokine responses induced by M. bovis BCG. Tuber. Lung Dis. 80, 197–207 (2000).
Wang, J., Wakeham, J., Harkness, R. & Xing, Z. Macrophages are a significant source of type 1 cytokines during mycobacterial infection. J. Clin. Invest. 103, 1023–1029 (1999).
Takayama, H. et al. Increased infiltration of tumor associated macrophages is associated with poor prognosis of bladder carcinoma in situ after intravesical bacillus Calmette-Guerin instillation. J. Urol. 181, 1894–1900 (2009).
Ayari, C. et al. Bladder tumor infiltrating mature dendritic cells and macrophages as predictors of response to bacillus Calmette-Guerin immunotherapy. Eur. Urol. 55, 1386–1395 (2009).
Hao, N. B. et al. Macrophages in tumor microenvironments and the progression of tumors. Clin. Dev. Immunol. 2012, 948098 (2012).
Beatty, J. D., Islam, S., North, M. E., Knight, S. C. & Ogden, C. W. Urine dendritic cells: a noninvasive probe for immune activity in bladder cancer? BJU Int. 94, 1377–1383 (2004).
Naoe, M. et al. Bacillus Calmette-Guerin-pulsed dendritic cells stimulate natural killer T cells and gammadeltaT cells. Int. J. Urol. 14, 532–538 (2007).
Higuchi, T. et al. A possible mechanism of intravesical BCG therapy for human bladder carcinoma: involvement of innate effector cells for the inhibition of tumor growth. Cancer Immunol. Immunother. 58, 1245–1255 (2009).
Hurwitz, A. A. & Watkins, S. K. Immune suppression in the tumor microenvironment: a role for dendritic cell-mediated tolerization of T cells. Cancer Immunol. Immunother. 61, 289–293 (2012).
McAveney, K. M., Gomella, L. G. & Lattime, E. C. Induction of TH1- and TH2-associated cytokine mRNA in mouse bladder following intravesical growth of the murine bladder tumor MB49 and BCG immunotherapy. Cancer Immunol. Immunother. 39, 401–406 (1994).
Luo, Y., Chen, X. & O'Donnell, M. A. Role of Th1 and Th2 cytokines in BCG-induced IFN-gamma production: cytokine promotion and simulation of BCG effect. Cytokine 21, 17–26 (2003).
Riemensberger, J., Bohle, A. & Brandau, S. IFN-gamma and IL-12 but not IL-10 are required for local tumour surveillance in a syngeneic model of orthotopic bladder cancer. Clin. Exp. Immunol. 127, 20–26 (2002).
Nepple, K. G., Lightfoot, A. J., Rosevear, H. M., O'Donnell, M. A. & Lamm, D. L. Bacillus Calmette-Guerin with or without interferon alpha-2b and megadose versus recommended daily allowance vitamins during induction and maintenance intravesical treatment of nonmuscle invasive bladder cancer. J. Urol. 184, 1915–1919 (2010).
Luo, Y. et al. Recombinant Mycobacterium bovis bacillus Calmette-Guerin (BCG) expressing mouse IL-18 augments Th1 immunity and macrophage cytotoxicity. Clin. Exp. Immunol. 137, 24–34 (2004).
Liu, W., O'Donnell, M. A., Chen, X., Han, R. & Luo, Y. Recombinant bacillus Calmette-Guerin (BCG) expressing interferon-alpha 2B enhances human mononuclear cell cytotoxicity against bladder cancer cell lines in vitro. Cancer Immunol. Immunother. 58, 1647–1655 (2009).
Arnold, J., de Boer, E. C., O'Donnell, M. A., Bohle, A. & Brandau, S. Immunotherapy of experimental bladder cancer with recombinant BCG expressing interferon-gamma. J. Immunother. 27, 116–123 (2004).
Bockholt, N. A. et al. Anti-interleukin-10R1 monoclonal antibody enhances bacillus Calmette-Guerin induced T-helper type 1 immune responses and antitumor immunity in a mouse orthotopic model of bladder cancer. J. Urol. 187, 2228–2235 (2012).
Ludwig, A. T. et al. Tumor necrosis factor-related apoptosis-inducing ligand: a novel mechanism for Bacillus Calmette-Guerin-induced antitumor activity. Cancer Res. 64, 3386–3390 (2004).
Kemp, T. J. et al. Neutrophil stimulation with Mycobacterium bovis bacillus Calmette-Guerin (BCG) results in the release of functional soluble TRAIL/Apo-2L. Blood 106, 3474–3482 (2005).
Zuiverloon, T. C. et al. Markers predicting response to bacillus Calmette-Guerin immunotherapy in high-risk bladder cancer patients: a systematic review. Eur. Urol. 61, 128–145 (2012).
Saint, F. et al. Prognostic value of a T helper 1 urinary cytokine response after intravesical bacillus Calmette-Guerin treatment for superficial bladder cancer. J. Urol. 167, 364–367 (2002).
Watanabe, E. et al. Urinary interleukin-2 may predict clinical outcome of intravesical bacillus Calmette-Guerin immunotherapy for carcinoma in situ of the bladder. Cancer Immunol. Immunother. 52, 481–486 (2003).
de Reijke, T. M., de Boer, E. C., Kurth, K. H. & Schamhart, D. H. Urinary cytokines during intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer: processing, stability and prognostic value. J. Urol. 155, 477–482 (1996).
Kaempfer, R. et al. Prediction of response to treatment in superficial bladder carcinoma through pattern of interleukin-2 gene expression. J. Clin. Oncol. 14, 1778–1786 (1996).
Thalmann, G. N. et al. Urinary Interleukin-8 and 18 predict the response of superficial bladder cancer to intravesical therapy with bacillus Calmette-Guerin. J. Urol. 164, 2129–2133 (2000).
Sagnak, L. et al. Predictive value of urinary interleukin-8 cutoff point for recurrences after transurethral resection plus induction bacillus Calmette-Guerin treatment in non-muscle-invasive bladder tumors. Clin. Genitourin. Cancer 7, E16–E23 (2009).
Kumar, A., Dubey, D., Bansal, P., Mandhani, A. & Naik, S. Urinary interleukin-8 predicts the response of standard and low dose intravesical bacillus Calmette-Guerin (modified Danish 1331 strain) for superficial bladder cancer. J. Urol. 168, 2232–2235 (2002).
Jo, E. K. Mycobacterial interaction with innate receptors: TLRs, C-type lectins, and NLRs. Curr. Opin. Infect. Dis. 21, 279–286 (2008).
Ayari, C., Bergeron, A., LaRue, H., Menard, C. & Fradet, Y. Toll-like receptors in normal and malignant human bladders. J. Urol. 185, 1915–1921 (2011).
Kleinnijenhuis, J., Oosting, M., Joosten, L. A., Netea, M. G. & Van Crevel, R. Innate immune recognition of Mycobacterium tuberculosis. Clin. Dev. Immunol. 2011, 405310 (2011).
Simons, M. P., Moore, J. M., Kemp, T. J. & Griffith, T. S. Identification of the mycobacterial subcomponents involved in the release of tumor necrosis factor-related apoptosis-inducing ligand from human neutrophils. Infect. Immun. 75, 1265–1271 (2007).
Tsuji, S. et al. Maturation of human dendritic cells by cell wall skeleton of Mycobacterium bovis bacillus Calmette-Guerin: involvement of toll-like receptors. Infect. Immun. 68, 6883–6890 (2000).
Kelley, D. R. et al. Prognostic value of purified protein derivative skin test and granuloma formation in patients treated with intravesical bacillus Calmette-Guerin. J. Urol. 135, 268–271 (1986).
Taniguchi, K. et al. Systemic immune response after intravesical instillation of bacille Calmette-Guerin (BCG) for superficial bladder cancer. Clin. Exp. Immunol. 115, 131–135 (1999).
Ratliff, T. L., Palmer, J. O., McGarr, J. A. & Brown, E. J. Intravesical Bacillus Calmette-Guerin therapy for murine bladder tumors: initiation of the response by fibronectin-mediated attachment of Bacillus Calmette-Guerin. Cancer Res. 47, 1762–1766 (1987).
Hudson, M. A., Brown, E. J., Ritchey, J. K. & Ratliff, T. L. Modulation of fibronectin-mediated Bacillus Calmette-Guerin attachment to murine bladder mucosa by drugs influencing the coagulation pathways. Cancer Res. 51, 3726–3732 (1991).
Zhao, W. et al. Role of a bacillus Calmette-Guerin fibronectin attachment protein in BCG-induced antitumor activity. Int. J. Cancer 86, 83–88 (2000).
Coplen, D. E., Brown, E. J., McGarr, J. & Ratliff, T. L. Characterization of fibronectin attachment by a human transitional cell carcinoma line, T24. J. Urol. 145, 1312–1315 (1991).
Kavoussi, L. R., Brown, E. J., Ritchey, J. K. & Ratliff, T. L. Fibronectin-mediated Calmette-Guerin bacillus attachment to murine bladder mucosa. Requirement for the expression of an antitumor response. J. Clin. Invest. 85, 62–67 (1990).
Schneider, B. et al. Specific binding of bacillus Calmette-Guerin to urothelial tumor cells in vitro. World J. Urol. 12, 337–344 (1994).
Bevers, R. F., Kurth, K. H. & Schamhart, D. H. Role of urothelial cells in BCG immunotherapy for superficial bladder cancer. Br. J. Cancer 91, 607–612 (2004).
Pan, C. W., Shen, Z. J. & Ding, G. Q. The effect of intravesical instillation of antifibrinolytic agents on bacillus Calmette-Guerin treatment of superficial bladder cancer: a pilot study. J. Urol. 179, 1307–1311 (2008).
Bevers, R. F., De Boer, E. C., Kurth, K. & Schamhart, D. H. BCG internalization in human bladder cancer cell lines, especially with regard to cell surface expressed fibronectin. Aktuelle Urologie 31, 31–34 (2000).
Becich, M. J., Carroll, S. & Ratliff, T. L. Internalization of bacille Calmette-Guerin by bladder tumor cells. J. Urol. 145, 1316–1324 (1991).
Kuroda, K., Brown, E. J., Telle, W. B., Russell, D. G. & Ratliff, T. L. Characterization of the internalization of bacillus Calmette-Guerin by human bladder tumor cells. J. Clin. Invest. 91, 69–76 (1993).
Durek, C. et al. Bacillus-Calmette-Guerin (BCG) and 3D tumors: an in vitro model for the study of adhesion and invasion. J. Urol. 162, 600–605 (1999).
Ernst, J. D. Macrophage receptors for Mycobacterium tuberculosis. Infect. Immun. 66, 1277–1281 (1998).
Redelman-Sidi, G., Iyer, G., Solit, D. B. & Glickman, M. S. Oncogenic activation of Pak1-dependent pathway of macropinocytosis determines BCG entry into bladder cancer cells. Cancer Res. 73, 1156–1167 (2013).
Huang, G., Redelman-Sidi, G., Rosen, N., Glickman, M. S. & Jiang, X. Inhibition of mycobacterial infection by the tumor suppressor PTEN. J. Biol. Chem. 287, 23196–23202 (2012).
Esuvaranathan, K. et al. Interleukin-6 production by bladder tumors is upregulated by BCG immunotherapy. J. Urol. 154, 572–575 (1995).
Bevers, R. F., de Boer, E. C., Kurth, K. H. & Schamhart, D. H. BCG-induced interleukin-6 upregulation and BCG internalization in well and poorly differentiated human bladder cancer cell lines. Eur. Cytokine Netw. 9, 181–186 (1998).
Zhang, G. J. et al. Autocrine IL-6 production by human transitional carcinoma cells upregulates expression of the alpha5beta1 firbonectin receptor. J. Urol. 163, 1553–1559 (2000).
Zhang, Y., Khoo, H. E. & Esuvaranathan, K. Effects of bacillus Calmette-Guerin and interferon alpha-2B on cytokine production in human bladder cancer cell lines. J. Urol. 161, 977–983 (1999).
de Reijke, T. M. et al. Cytokine production by the human bladder carcinoma cell line T24 in the presence of bacillus Calmette-Guerin (BCG). Urol. Res. 21, 349–352 (1993).
Lattime, E. C., Gomella, L. G. & McCue, P. A. Murine bladder carcinoma cells present antigen to BCG-specific CD4+ T-cells. Cancer Res. 52, 4286–4290 (1992).
Jackson, A. M. et al. Induction of ICAM 1 expression on bladder tumours by BCG immunotherapy. J. Clin. Pathol. 47, 309–312 (1994).
Prescott, S. et al. HLA-DR expression by high grade superficial bladder cancer treated with BCG. Br. J. Urol. 63, 264–269 (1989).
el-Demiry, M. I. et al. Local immune responses after intravesical BCG treatment for carcinoma in situ. Br. J. Urol. 60, 543–548 (1987).
Ikeda, N., Toida, I., Iwasaki, A., Kawai, K. & Akaza, H. Surface antigen expression on bladder tumor cells induced by bacillus Calmette-Guerin (BCG): A role of BCG internalization into tumor cells. Int. J. Urol. 9, 29–35 (2002).
Videira, P. A. et al. Efficacy of bacille Calmette-Guerin immunotherapy predicted by expression of antigen-presenting molecules and chemokines. Urology 74, 944–950 (2009).
Chen, F., Zhang, G., Iwamoto, Y. & See, W. A. BCG directly induces cell cycle arrest in human transitional carcinoma cell lines as a consequence of integrin cross-linking. BMC Urol. 5, 8 (2005).
Jackson, A. et al. Bacillus-calmette-guerin (bcg) organisms directly alter the growth of bladder-tumor cells. Int. J. Oncol. 5, 697–703 (1994).
Pook, S. H., Rahmat, J. N., Esuvaranathan, K. & Mahendran, R. Internalization of Mycobacterium bovis, Bacillus Calmette Guerin, by bladder cancer cells is cytotoxic. Oncol. Rep. 18, 1315–1320 (2007).
See, W. A. et al. Bacille-Calmette Guerin induces caspase-independent cell death in urothelial carcinoma cells together with release of the necrosis-associated chemokine high molecular group box protein 1. BJU Int. 103, 1714–1720 (2009).
Sandes, E. et al. Cathepsin B is involved in the apoptosis intrinsic pathway induced by Bacillus Calmette-Guerin in transitional cancer cell lines. Int. J. Mol. Med. 20, 823–828 (2007).
Sasaki, A., Kudoh, S., Mori, K., Takahashi, N. & Suzuki, T. Are BCG effects against urinary bladder carcinoma cell line T24 correlated with apoptosis in vitro? Urol. Int. 59, 142–148 (1997).
The authors declare no competing financial interests.
About this article
Cite this article
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
Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence
International Urology and Nephrology (2020)
Nature Reviews Urology (2020)
Biological Chemistry (2020)
An immune relevant signature for predicting prognoses and immunotherapeutic responses in patients with muscle‐invasive bladder cancer (MIBC)
Cancer Medicine (2020)