Friday, April 25, 2014

BCG For Bladder Cancer: Why it Works, How it Works

Macrophage engulfing
Bacillus Calmette-Guérin
Nearly 60,000 patients are diagnosed with urothelial cancer (UC) of the bladder each year and 300-500,00 survivors are living in the United States.  The majority of these cancers (>70%) are non-muscle invasive disease, however 40-80% of these tumors will recur within the first year and 10-25% will develop muscle-invasive disease [1]. Intravesical treatments after transurethral resection (TUR) are the mainstay of treatment for non-muscle invasive urothelial cancer (NMIUC), and Bacillus Calmette-Guerin (BCG) immunotherapy is the standard, most commonly used intravesical treatment.  

Despite its long-history of efficacy in the treatment of NMIUC, the mechanism of action of BCG is not well-defined.  Subsequently, it is not clear to many patients and practitioners why BCG works.  Here we review what is known about the mechanism of action of BCG for NMIUC.

BCG is a live attenuated strain of Mycobacterium bovis, a bacteria very similar to tuberculosis.  When in contact with the urothelium (lining of the urinary system), BCG elicits a variety of local immune responses which appear to correlate with its anti-tumor activity.  The role of the immune system in the action of BCG was clear even from the seminal work demonstrating the anti-cancer effects of BCG in 1959.[2]  Since then, additional studies demonstrate the importance of the immune system in the mechanism of BCG:

  • A competent host immune system is required for BCG to work [3,4]
  • Viable BCG is required for a response [5,6]
  • More than 40% of patients receiving intravesical BCG instillation experience conversion of a previously negative tuberculin skin test.[7]
  • BCG "priming" (exposing a patient to BCG prior to treatment) may improve response rates to intravesical BCG.[8]
    • Mice immunized subcutaneously with BCG have improved survival, compared with BCG-naive mice, after intravesical BCG therapy. 
    • Patients with a pre-existing positive tuberculin skin test have better recurrence-free-survival rates than those without, after intravesical BCG therapy.

MECHANISM OF bcg-mediated immune response IN TREATING BLADDER CANCER

The initial activating step for the inflammatory cascade is binding of BCG to fibronectin (a protein that helps the cell bind molecules) expressed on the urothelium [9]. The BCG is then internalized by both normal urothelial and cancer cells.  The host's immune system, through antigen presenting cells (APCs: specifically macrophages and dendritic cells), identifies components of BCG as foreign to the host.  Macrophages are the initial line of defense, allowing for cytokine production, BCG antigen presentation, and function in an anti-neoplastic manner against bladder cancer cells [10]. Along with its anti-BCG effects, macrophages also kill cancer cells through direct cell-to-cell contact as well as the release of the cytokines TNF-α and IFN-γ; and the molecule nitric oxide [11].

Once macrophages and dendritic cells identify components of BCG as foreign, these components are presented as BCG antigens (an antigen is any substance that provokes an immune response) via the MHC (major histocompatibility complex) II leading to a huge immune response.  The immune response is mediated through the T-helper (Th) 1 immune response, causing the release of cytokines (proteins used by cells to transmit signals to other cells) that attract more immune cells (neutrophils, lymphocytes, natural killer (NK) cells, macrophages, and dendritic cells) into the wall of the bladder.[12]  The Th1 cytokine profile (IFN-γ, IL-2, IL-12) has been demonstrated as necessary for a successful response to BCG; while the alternative Th2 pathway and related cytokines (IL10) are correlated with BCG failure.[13]

Neutrophils are another important cell in the BCG response pathway.  Neutrophils become activated and elicit production of tumor necrosis factor-related apoptosis-induced ligand (TRAIL) which specifically targets the malignant bladder cells. A significantly higher level of urinary TRAIL is seen in patients responding to BCG therapy than in non-responders [14]. A systemic immune response is also seen in the form of elevated serum cytokines, cellular and humoral BCG reactivity with in vivo evidence pointing to involvement of CD4+ and CD8+ lymphocytes, NK cells, and granulocytes.[15,16]
From Luo Y et al. [10]

This entry was written by Nilay M. Gandhi, MD, senior assistant resident at the Brady Urological Institute at Johns Hopkins.  

Some of the data is extracted from the chapter Intravesical Immunotherapy - Bladder Cancer: Diagnosis and Clinical Management by Nilay M. Gandhi, Laura A. Bertrand, Donald L. Lamm, and Michael A. O’Donnell which will appear in newest edition of The Textbook of Bladder Cancer.

[1] Kemp TJ, Ludwig AT, Earel JK, et al. Neutrophil stimulation with Mycobacterium bovis bacillus Calmette-Guérin (BCG) results in the release of functional soluble TRAIL/Apo-2L. Blood 2005; 106: 3474-82.
[2] 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).
[3] Zbar, B. & Rapp, H. J. Immunotherapy of guinea pig cancer with BCG. Cancer 34 (Suppl.), 1532–1540 (1974).
[4] 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).
[5] Zbar, B. & Tanaka, T. Immunotherapy of cancer: regression of tumors after intralesional injection of living Mycobacterium bovis. Science 172, 271–273 (1971).
[6] 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).
[7] 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).
[8] Biot, C. et al. Preexisting BCG-specific T cells improve intravesical immunotherapy for bladder cancer. Sci. Transl. Med. 4, 137ra72 (2012).
[9] Kavoussi LR, Brown EJ, Ritchey JK, and Ratliff TL. Fibronectin-mediated Calmette-Guerin bacillus attachment to murine bladder mucosa. Requirement for the expression of an antitumor response. Journal of Clinical Investigation 1990; 85 (1): 62-67.
[10] Luo Y, Askeland EJ, Newton MR, et al. Immunotherapy of Urinary Bladder Carcinoma: BCG and Beyond, Cancer Treatment - Conventional and Innovative Approaches, Prof. Letícia Rangel (Ed.), ISBN: 978-953-51-1098-9, InTech, DOI: 10.5772/55283.
[11] Luo Y, Yamada H, Chen X, et al. Recombinant Mycobacterium bovis bacillus Calmette- Guérin (BCG) expressing mouse IL-18 augments Th1 immunity and macrophage cytotoxity. Clin Exp Immunol 2004; 137: 24-34.
[12] Askeland EJ, Newton MR, O’Donnell MA, Luo Y. Bladder cancer immunotherapy: BCG and beyond. Adv Urol 2012; article ID 181987.
[13] Saint F, Patard JJ, Maille P, et al. Prognostic value of a T helper 1 urinary cytokine response after intravesical bacillus Calmette-Guerin treatment for superficial bladder cancer. J Urol 2002; 167 (1): 364-7.
[14] Ludwig AT, Moore JM, Luo Y, et al. Tumor necrosis factor-related apoptosis-inducing ligand: A novel mechanism for bacillus Calmette-Guerin-induced antitumor activity. Cancer Res 2004; 64 (10): 3386-90.
[15] Lamm DL, Thor DE, Winters WD, et al. BCG immunotherapy of bladder cancer: inhibition of tumor recurrence and associated immune responses. Cancer 1981; 48 (1):82-88.
[16] Gil Redelman-Sidi,  Michael S. Glickman, and Bernard H. Bochner.  The mechanism of action of BCG therapy for bladder cancer—a current perspective.  Nature Reviews Urology 11, 153–162 (2014) doi:10.1038/nrurol.2014.15

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