Wednesday, July 16, 2014

BCG Immunotherapy Alternatives

Nearly 300,000 patients are diagnosed with urothelial cancer (UC) of the bladder each year 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.

When and if BCG fails, patients are left with the difficult choice of proceeding to radical surgery or, often unproven, additional intravesical therapies.  Here we present some of the data on additional immunotherapies for the treatment of bladder cancer.


Interferons are glycoproteins with a number of anti-viral properties.  IFN-α (interferon-alpha) is known to stimulate NK (natural killer) cells, induce MHC (major histocompatibility complex) class I response, augments the ability of Th1 (T-helper cells) and increase antibody recognition -- all mechanisms that stimulate the immune response in the bladder [2,3]. 
See our prior blog on BCG For Bladder Cancer: Why it Works, How it Works for a better understanding of stimulating the immune system for the treatment of bladder cancer.
The ability of IFN-α to fight off cancers has been attributed to both an ability to stop cell growth and its immunomodulatory effects.  Because of its ability to augment the local immune response, IFN-α2b has been studied in conjunction with BCG.  There is only one published, randomized trial comparing BCG alone to BCG+IFN.  This group of patients did not receive any prior intravesical treatments, and there was no significant difference in recurrence-free survival at two years, although the IFN group did exhibit a higher incidence of constitutional symptoms and fever [4].

IFN-α may play a role in patients who have failed an initial course of intravesical BCG therapy.  A study of 40 patients failing one or more courses of BCG showed a disease-free rate of 53% at 24 months when they went on to receive 6-8 weekly instillations of low-dose BCG plus IFN-α [5].  A multicenter trial including 467 patients with previous BCG failure demonstrated a disease-free rate of 45% after being treated with reduced-dose BCG and IFN-α [6].  Risk factors for recurrence were stage T1, tumor size >5 cm, multifocality, more than one prior BCG failure and age >80.

Timing of recurrence predicts effectiveness of BCG, IFN-α combination therapy.  Patients with recurrence >12 months after initial BCG treatment who were treated with low-dose BCG plus IFN-α had a disease-free rate of 53-66% at 24 months.  However, patients with recurrence within one year did poorly, with a disease-free rate of 34-43% at two years.[7]

Therefore, combination therapy with both BCG and IFN-α may have a salvage role in patients with single course BCG failure or late relapse, while those who recur quickly after initial BCG treatment may be destined to failure and better served by radical cystectomy.


Interleukin (IL)-2 is a cytokine that enhances the production of cytotoxic lymphocytes capable of lysing tumor cells while leaving benign cells unharmed -- IL-2 activated lymphocytes are known as “lymphocyte-activated killer” or LAK cells [8,9].  Additionally, IL-2 augments the immune system through a variety of interactions with NK cells, monocytes and Th1 cells [9,10].

IL-2 is poorly tolerated when given systemically, however intravesical administration has a much improved side effect profile [11,12]. In a small cohort, intravesical IL-2 administered after incomplete TUR of low grade T1 papillary UC demonstrated regression of the “marker lesion” in 8 of 10 patients [13].  Animal models with recombinant IL-2-secreting strains of BCG have shown an enhanced antitumor cytotoxicity and local immune response when compared with BCG alone [14-16].


Interleukin-12 (IL-12) is known to be synergistic with IL-2 since the 1980's, and has therefore been the subject of considerable cancer research.  Multiple animal studies have shown tumor responsiveness to IL-12, including bladder cancer models [17-19].  In mice, bladder cancers responded to intravesical treatments of IL-12 and BCG, the levels of urinary IFN-α were noted to be significantly increased after therapy, and immune reaction dampened when IL-12 was neutralized. [20-22].  However, a recent Phase I monotherapy trial of intravesical IL-12 in humans, failed to show any clinical effectiveness [23].


Interleukin-10 (IL-10) is an inhibitor of immune response, decreasing the production of several cytokines produced by Th1, including IFN-γ [24].  Several initial studies demonstrated an improved BCG and local immune response in IL-10 knockout mice after being inoculated with bladder cancer with greater antitumor activity and prolonged survival [10, 25, 26].  Therefore, more recent research has attempted to block the IL-10 receptor.  Mice treated with BCG and an anti-IL-10 receptor antibody show improved overall and tumor-free survival when compared to BCG controls -- although not all of these differences reached statistical significance [27]. Further testing showing more confirmatory results is necessary but these initial results are promising.


  • Interferon-alpha may be effective for patients who have failed an initial course of BCG.
    • IFN-α is not more effective than BCG alone for initial treatment.
    • Patients who recur quickly after the first dose of BCG are less likely to benefit from IFN-α.
  • Interleukin-2 and -12 have immunostimulatory effects and have demonstrate some efficacy for treating bladder cancer in animal models.
  • Interleukin-10 is an inhibitor of immune response and animal studies blocking this cytokine have promising early results. 

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.

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[2] Kamat AM, Lamm DL. Immunotherapy for bladder cancer. Curr Urol Rep 2001; 2: 62-9.
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[4] Nepple KG, Lightfoot AJ, Rosevear HM, et al; Bladder Cancer Genitourinary Oncology Study Group.  Bacillus Calmette-Guérin with or without interferon α-2b and megadose versus recommended daily allowance vitamins during induction and maintenance intravesical treatment of nonmuscle invasive bladder cancer. J Urol 2010; 184: 1915-9.
[5] O’Donnell MA, Krohn J, DeWolf WC. Salvage intravesical therapy with interferon-alpha-2b plus low dose bacillus Calmette-Guérin is effective in patients with superficial bladder cancerin whom bacillus Calmette-Guérin alone previously failed. J Urol 2001; 166: 1300-4.
[6] Joudi FN, Smith BJ, O’Donnell MA. National BCG-Interferon Phase II Investigator Group Final results from a national multi-center phase II trial of combination bacillus Calmette-Guérin plus interferon α-2b for reducing recurrence of superficial bladder cancer. Urol Oncol 2006; 24: 344-8.
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[8] Yron I, Wood TA, Spiess PJ, et al. In vitro growth of murine T cells v. the isolation and growth of lymphoid cells infiltrating syngeneic solid tumors. J Immunol 1980; 125: 238-45.
[9] Lotze MT, Grimm EA, Mazunder A. Lysis of fresh and cultured autologous tumor by human lymphocytes cultures in T-cell growth factor. Cancer Res 1981; 41: 4420-5.
[10] Henney CS, Kuribayashi K, Kern DE, et al. Interleukin-2 augments natural killer cell activity. Nature 1981; 291: 335-8.
[11] Malkovsky M, Loveland B, North M. Recombinant interleukin-2 directly augments the cytotoxicity of human monocytes. Nature 1987; 325: 262-5.
[12] Tubaro A, Velotti F, Stoppacciaro A, et al. Continuous intra-arterial administration of recombinant interleukin-2 in low stage bladder cancer: a phase 1B study. Cancer 1991; 68: 56-61.
[13] Gomella LG, McGinnis DE, Lattime EC, et al. Treatment of transitional cell carcinoma of the bladder with intravesical interleukin-2: a pilot study. Cancer Biother 1993; 8: 223-7.
[14] Den Otter W, Dobrowolski  Z, Bugajski A, et al. Intravesical interleukin-2 in T1 papillary bladder carcinoma: regression of marker lesion in 8 of 10 patients. J Urol 1998; 159: 1183-6.
[15] O’Donnell MA, Aldovini A, Duda RB et al. Recombinant Mycobacterium bovis BCG secreting functional interleukin-2 enhances gamma interferon production by splenocytes.  Infect Immun 1994; 62: 2508-14.
[16] Yamada H, Matsumoto S, Matsumoto T, et al. Murine IL-2 secreting recombinant bacillus Calmette-Guérin augments macrophage-mediated cytotoxicity against murine bladder cancer MBT-2. J Urol 2000; 164: 526-31.
[17] Gately MK, Desai BB, Wolitzky AG, et al. Regulation of human lymphocyte proliferation by a heterodimeric cytokine, IL-12 (cytotoxic lymphocyte maturation factor). J Immunol 1991; 147: 874-82.
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[19] Teicher BA, Ara G, Buxton D,et al. Optimal scheduling of interleukin-12 and chemotherapy in the murine MB-49 bladder carcinoma and B16 melanoma. Clin Cancer Res 1997; 3: 1661-7.
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[21] O’Donnell MA, Luo Y, Hunter SE, et al. The essential role of interferon-gamma during interleukin-12 therapy for murine transitional cell carcinoma of the bladder. J Urol 2004; 171: 1336-42.
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[23] Weiss GR, O’Donnell MA, Loughlin, K, et al. Phase I study of the intravesical administration of recombinant human interleukin-12 in patients with recurrent superficial transitional cell carcinoma of the bladder. J Immunother 2003; 26: 343-8.
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[25] Nadler R, Luo Y, Zhao W, et al. Interleukin-10 induced augmentation of delayed-type hypersensitivity (DTH) enhances Mycobacterium bovis bacillus Calmette-Guérin (BCG) mediated antitumor activity. Clin Exp Immunol 2003; 131: 206-16.
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[27] Bockholt NA, Knudson MJ, Henning J, et al. Anti-IL-10R1 monoclonal antibody enhances BCG-induced Th1 immune responses and antitumor immunity in a mouse orthotopic model of bladder cancer. J Urol 2012; 187: 2228-35.


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