Adjuvant Treatment: Old and New Immunotherapy in Non-Muscle-Invasive Bladder Cancer

  • J. PalouEmail author
  • F. Pisano


Bacillus Calmette-Guérin (BCG) is the first connection between bladder cancer and immunotherapy and still represents the gold standard treatment for intermediate and high-risk non-muscle-invasive bladder cancer (NMIBC). However, the use of intravesical BCG alone in high-risk NMIBC patients seems to be insufficient, as showed by the relative high numbers of “BCG failure” patients. Since BCG induces infiltration of the bladder wall by neutrophils, which play an important role in the antitumor effect of BCG itself, and the release of IL-15, which plays a crucial role in neutrophil activation and migration, the use of recombinant BCG strain expressing some interleukins has been proposed, with interesting results. Gene therapy is a promising and attractive strategy for cancer biotherapy and some authors have already pointed out the potential antitumor effect exerted by the intravesical application of oncoviruses. Gene therapy and anticancer vaccines represent probably the greatest challenges in bladder cancer research, but their clinical application remains, to date, very far away.


BCG Immunotherapy Non-muscle invasive bladder cancer Gene therapy Oncovirus 


  1. 1.
    Abdollah F, Gandaglia G, Thuret R, Schmitges J, Tian Z, Jeldres C, et al. Incidence, survival and mortality rates of stage-specific bladder cancer in United States: a trend analysis. Cancer Epidemiol. 2013;37:219–25.CrossRefPubMedGoogle Scholar
  2. 2.
    Decker WK, Safdar A. Bioimmunoadjuvants for the treatment of neoplastic and infectious disease: Coley’s legacy revisited. Cytokine Growth Factor Rev. 2009;20:271–81.CrossRefPubMedGoogle Scholar
  3. 3.
    Bellmunt J, Powels T, Vogelzang NJ. A review on the revolution of PD-1/PD-L1 immunotherapy for bladder cancer: the future is now. Cancer Treat Rev. 2017;54:58–67.CrossRefPubMedGoogle Scholar
  4. 4.
    Finn OJ. Cancer immunology. N Engl J Med. 2008;358:2704–15.CrossRefPubMedGoogle Scholar
  5. 5.
    Teicher BA. Transforming growth factor-beta and the immune response to malignant disease. Clin Cancer Res. 2007;13:6247–51.CrossRefPubMedGoogle Scholar
  6. 6.
    Herr HW, Morales A. History of bacillus Calmette–Guerin and bladder cancer: an immunotherapy success story. J Urol. 2008;179:53–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976;116:180.CrossRefGoogle Scholar
  8. 8.
    Lockyer CR, Gillatt DA. BCG immunotherapy for superficial bladder cancer. J R Soc Med. 2001;94:119–23.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Sapre N, Corcoran NM. Modulating the immune response to Bacillus Calmette-Guerin (BCG): a novel way to increase the immunotherapeutic effect of BCG for treatment of bladder cancer. BJU Int. 2013;112:852–3.CrossRefPubMedGoogle Scholar
  10. 10.
    Babjuk M, Böhle A, Burger M, Capoun O, Cohen D, Compérat EM, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. Eur Urol. 2017;71:447–61.CrossRefPubMedGoogle Scholar
  11. 11.
    Kavoussi LR, Brown EJ, Ritchey JK, Ratliff TL. Fibronectin-mediated Calmette-Guerin bacillus attachment to murine bladder mucosa. Requirement for the expression of an antitumor response. J Clin Invest. 1990;85:62–7.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Solsona E, Madero R, Chantada V, Fernandez JM, Zabala JA, Portillo J, et al. A. Sequential combination of mitomycin C plus Bacillus Calmette-Guérin (BCG) is more effective but more toxic than BCG alone in patients with non-muscle-invasive bladder cancer in intermediate- and high-risk patients: final outcome of CUETO 93009, a randomized prospective trial. Eur Urol. 2015;67:508–16.CrossRefPubMedGoogle Scholar
  13. 13.
    Di Stasi SM, Giannantoni A, Giurioli A, Valenti M, Zampa G, Storti L, et al. Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial. Lancet Oncol. 2006;7:43–51.CrossRefPubMedGoogle Scholar
  14. 14.
    Suttmann H, Riemensberger J, Bentien G, Schmaltz D, Stöckle M, Jocham D, et al. Neutrophil granulocytes are required for effective Bacillus Calmette-Guerin immunotherapy of bladder cancer and orchestrate local immune responses. Cancer Res. 2006;66:8250–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Takeuchi A, Dejima T, Yamada H, Shibata K, Nakamura R, Eto M, et al. IL17 production by γδ T cells is important for the antitumor effect of Mycobacterium bovis Bacillus Calmette-Guérin treatment against bladder cancer. Eur J Immunol. 2011;41:246–51.CrossRefPubMedGoogle Scholar
  16. 16.
    Waldmann TA. The shared and contrasting roles of IL2 and IL15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy. Cancer Immunol Res. 2015;3:219–27.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Takeuchi A, Eto M, Tatsugami K, Shiota M, Yamada H, Kamiryo Y, et al. Antitumor activity of recombinant Bacille Calmette-Guérin secreting interleukin-15-Ag85B fusion protein against bladder cancer. Int Immunopharmacol. 2016;35:327–31.CrossRefPubMedGoogle Scholar
  18. 18.
    Gomes-Giacoia E, Miyake M, Goodison S, Sriharan A, Zhang G, You L, et al. Intravesical ALT-803 and BCG treatment reduces tumor burden in a carcinogen induced bladder cancer rat model; a role for cytokine production and NK cell expansion. PLoS One. 2014;9:e96705.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Zhou TC, Sankin AI, Porcelli SA, Perlin DS, Schoenberg MP, Zang X. A review of the PD-1/PD-L1 checkpoint in bladder cancer: from mediator of immune escape to target for treatment. Urol Oncol. 2016;35:14–20.CrossRefPubMedGoogle Scholar
  20. 20.
    Nakanishi J, Wada Y, Matsumoto K, Azuma M, Kikuchi K, Ueda S. Overexpression of B7–H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother. 2007;56:1173–82.CrossRefPubMedGoogle Scholar
  21. 21.
    Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti- PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515:558–62.CrossRefPubMedGoogle Scholar
  22. 22.
    Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387:1909–20.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Sharma P, Callahan MK, Bono P, Kim J, Spiliopoulou P, Calvo E, et al. Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol. 2016;17:1590–8.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Plimack ER, Bellmunt J, Gupta S, Berger R, Montgomery RB, Heath K, et al. Pembrolizumab (MK-3475) for advanced urothelial cancer: updated results and biomarker analysis from KEYNOTE-012. Chicago: American Society of Clinical Oncology; 2015. Abstr. p. 4502.Google Scholar
  25. 25.
    Balar A, Bellmunt J, O’Donnell PH, Castellano D, Grivas P, Vuky J, et al. Pembrolizumab (pembro) as first-line therapy for advanced/unresectable or metastatic urothelial cancer: preliminary results from the phase 2 KEYNOTE-052 study. Copenhagen: European Society for Medical Oncology. Proceedings of ESMO; 2016. Abstr LBA32_PR.Google Scholar
  26. 26.
    Zhai Z, Wang Z, Fu S, Lu J, Wang F, Li R, et al. Antitumor effects of bladder cancer-specific adenovirus carrying E1A-androgen receptor in bladder cancer. Gene Ther. 2012;19:1065–74.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Burke JM, Lamm DL, Meng MV, Nemunaitis JJ, Stephenson JJ, Arseneau JC, et al. A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. J Urol. 2012;188:2391–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Castillo-Martin M, Domingo-Domenech J, Karni-Schmidt O, Matos T, Cordon-Cardo C. Molecular pathways of urothelial development and bladder tumorigenesis. Urol Oncol. 2010;28:401–8.CrossRefPubMedGoogle Scholar
  29. 29.
    Kowalski M, Jones N, Jewett MAS, et al. Treatment with intravesical Vicinium™. Results in durable responses in patients with carcinoma in situ (CIS) previously treated with BCG. Paper presented at the 30th Congress of the Société Internationale d’Urologie; November 1–5; Shanghai, China. 2009.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of UrologyFundació Puigvert, Universitat Autònoma de BarcelonaBarcelonaSpain

Personalised recommendations