The development of interferon-based gene therapy for BCG unresponsive bladder cancer: from bench to bedside

  • Jonathan J. Duplisea
  • Sharada Mokkapati
  • Devin Plote
  • Kimberly S. Schluns
  • David J. McConkey
  • Seppo Yla-Herttuala
  • Nigel R. Parker
  • Colin P. DinneyEmail author
Invited Review


Background and Purpose

BCG unresponsive bladder cancer is an inherently resistant disease state for which the preferred treatment is radical cystectomy. To date, no effective intravesical therapies exist for patients who possess these resistant tumors. For this reason, many research groups are actively investigating/testing novel therapeutic agents to aid in bladder preservation for this patient population. This review article describes our 15-year experience developing and testing IFN-based gene therapy.


A comprehensive review was performed of all studies pertaining to IFN-based gene therapy for non-muscle invasive bladder cancer from 2003 to 2018.

Results and Conclusions

Over the past two decades, gene therapy has evolved into a powerful tool in our fight against cancer. After overcoming the initial barriers associated with gene delivery to the bladder, we have made significant strides forward in developing this novel therapeutic strategy for the treatment of this inherently resistant disease state. Our results to date are very encouraging; however, much work lies ahead to better understand and optimize this novel approach for treating non-muscle invasive bladder.


BCG unresponsive bladder cancer Gene therapy Interferon-α Instiladrin 


Author contributions

JD literature review and manuscript writing. SM manuscript editing/data collection. DP manuscript editing/data collection. KS manuscript editing. SYH manuscript writing/editing. NP manuscript writing/editing. CD manuscript oversight/writing/editing.


The University of Texas MD Anderson SPORE in Genitourinary Cancer P50CA091846, NIH/NCI under P30CA016672.

Compliance with ethical standards

Conflict of interest

Nigel Parker: leadership, consulting, and research funding—FKD Therapies Oy. Seppo Yla-Herttulla: consultant for FKD Therapies Oy. Colin Dinney: consultant on advisory board for FKD Therapies Oy. All remaining authors declare no conflicts of interest.

Research involving human participants and/or animals

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Informed consent

Informed consent was obtained from all individual participants of clinical studies included in this review article.


  1. 1.
    Kaufman DS, Shipley WU, Feldman AS (2009) Bladder cancer. Lancet (Lond, Engl) 374(9685):239–249. CrossRefGoogle Scholar
  2. 2.
    Siegel RL, Miller KD, Jemal A (2017) Cancer statistics 2017. CA Cancer J Clin 67(1):7–30. CrossRefPubMedGoogle Scholar
  3. 3.
    Babjuk M, Bohle A, Burger M, Capoun O, Cohen D, Comperat EM, Hernandez V, Kaasinen E, Palou J, Roupret M, van Rhijn BW, Shariat SF, Soukup V, Sylvester RJ, Zigeuner R (2017) EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. Eur Urol 71(3):447–461. CrossRefPubMedGoogle Scholar
  4. 4.
    Chang SS, Boorjian SA, Chou R, Clark PE, Daneshmand S, Konety BR, Pruthi R, Quale DZ, Ritch CR, Seigne JD, Skinner EC, Smith ND, McKiernan JM (2016) Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline. J Urol 196(4):1021–1029. CrossRefPubMedGoogle Scholar
  5. 5.
    Spiess PE, Agarwal N, Bangs R, Boorjian SA, Buyyounouski MK, Clark PE, Downs TM, Efstathiou JA, Flaig TW, Friedlander T, Greenberg RE, Guru KA, Hahn N, Herr HW, Hoimes C, Inman BA, Jimbo M, Kader AK, Lele SM, Meeks JJ, Michalski J, Montgomery JS, Pagliaro LC, Pal SK, Patterson A, Plimack ER, Pohar KS, Porter MP, Preston MA, Sexton WJ, Siefker-Radtke AO, Sonpavde G, Tward J, Wile G, Dwyer MA, Gurski LA (2017) Bladder cancer, version 5.2017, NCCN clinical practice guidelines in oncology. J Nat Compr Cancer Netw JNCCN 15(10):1240–1267. CrossRefGoogle Scholar
  6. 6.
    Jarow J, Maher VE, Tang S, Ibrahim A, Kim G, Sridhara R, Pazdur R (2015) Development of systemic and topical drugs to treat non-muscle invasive bladder cancer. Bladder Cancer (Amst, Neth) 1(2):133–136. CrossRefGoogle Scholar
  7. 7.
    Prout GR Jr, Koontz WW Jr, Coombs LJ, Hawkins IR, Friedell GH (1983) Long-term fate of 90 patients with superficial bladder cancer randomly assigned to receive or not to receive thiotepa. J Urol 130(4):677–680CrossRefGoogle Scholar
  8. 8.
    Steinberg G, Bahnson R, Brosman S, Middleton R, Wajsman Z, Wehle M (2000) Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. The Valrubicin Study Group. J Urol 163(3):761–767CrossRefGoogle Scholar
  9. 9.
    Kamat AM, Colombel M, Sundi D, Lamm D, Boehle A, Brausi M, Buckley R, Persad R, Palou J, Soloway M, Witjes JA (2017) BCG-unresponsive non-muscle-invasive bladder cancer: recommendations from the IBCG. Nat Rev Urol 14(4):244–255. CrossRefPubMedGoogle Scholar
  10. 10.
    Steinberg RL, Thomas LJ, Mott SL, O’Donnell MA (2016) Bacillus Calmette-Guerin (BCG) treatment failures with non-muscle invasive bladder cancer: a data-driven definition for BCG unresponsive disease. Bladder Cancer (Amst, Neth) 2(2):215–224. CrossRefGoogle Scholar
  11. 11.
    Nieder AM, Brausi M, Lamm D, O’Donnell M, Tomita K, Woo H, Jewett MA (2005) Management of stage T1 tumors of the bladder: International Consensus Panel. Urology 66(6 Suppl 1):108–125. CrossRefPubMedGoogle Scholar
  12. 12.
    Lerner SP, Dinney C, Kamat A, Bivalacqua TJ, Nielsen M, O’Donnell M, Schoenberg MP, Steinberg G (2015) Clarification of bladder cancer disease states following treatment of patients with intravesical BCG. Bladder Cancer (Amster, Neth) 1(1):29–30. CrossRefGoogle Scholar
  13. 13.
    US Department of Health and Human Service Food and Drug administration (2018) BCG unresponsive non-muscle invasive bladder cancer—developing drugs and biologics for treatment—a guideline for industry.
  14. 14.
    Siddiqui MR, Grant C, Sanford T, Agarwal PK (2017) Current clinical trials in non-muscle invasive bladder cancer. Urol Oncol 35(8):516–527. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Papageorgiou A, Dinney CP, McConkey DJ (2007) Interferon-alpha induces TRAIL expression and cell death via an IRF-1-dependent mechanism in human bladder cancer cells. Cancer Biol Ther 6(6):872–879CrossRefGoogle Scholar
  16. 16.
    von Marschall Z, Scholz A, Cramer T, Schafer G, Schirner M, Oberg K, Wiedenmann B, Hocker M, Rosewicz S (2003) Effects of interferon alpha on vascular endothelial growth factor gene transcription and tumor angiogenesis. J Natl Cancer Inst 95(6):437–448CrossRefGoogle Scholar
  17. 17.
    Dinney CP, Bielenberg DR, Perrotte P, Reich R, Eve BY, Bucana CD, Fidler IJ (1998) Inhibition of basic fibroblast growth factor expression, angiogenesis, and growth of human bladder carcinoma in mice by systemic interferon-alpha administration. Can Res 58(4):808–814Google Scholar
  18. 18.
    Slaton JW, Perrotte P, Inoue K, Dinney CP, Fidler IJ (1999) Interferon-alpha-mediated down-regulation of angiogenesis-related genes and therapy of bladder cancer are dependent on optimization of biological dose and schedule. Clin Cancer Res 5(10):2726–2734PubMedGoogle Scholar
  19. 19.
    Joudi FN, Smith BJ, O’Donnell MA (2006) Final results from a national multicenter phase II trial of combination bacillus Calmette-Guerin plus interferon alpha-2B for reducing recurrence of superficial bladder cancer. Urol Oncol 24(4):344–348. CrossRefPubMedGoogle Scholar
  20. 20.
    Lamm D, Brausi M, O’Donnell MA, Witjes JA (2014) Interferon alfa in the treatment paradigm for non-muscle-invasive bladder cancer. Urol Oncol 32(1):35.e21–35.e30. CrossRefGoogle Scholar
  21. 21.
    Malmstrom PU (2002) A randomized comparative dose-ranging study of interferon-alpha and mitomycin-C as an internal control in primary or recurrent superficial transitional cell carcinoma of the bladder. BJU Int 89(7):681–686CrossRefGoogle Scholar
  22. 22.
    Rajala P, Kaasinen E, Raitanen M, Liukkonen T, Rintala E (2002) Perioperative single dose instillation of epirubicin or interferon-alpha after transurethral resection for the prophylaxis of primary superficial bladder cancer recurrence: a prospective randomized multicenter study–FinnBladder III long-term results. J Urol 168(3):981–985. CrossRefPubMedGoogle Scholar
  23. 23.
    Torti FM, Shortliffe LD, Williams RD, Pitts WC, Kempson RL, Ross JC, Palmer J, Meyers F, Ferrari M, Hannigan J et al (1988) Alpha-interferon in superficial bladder cancer: a Northern California Oncology Group Study. J Clin Oncol 6(3):476–483. CrossRefPubMedGoogle Scholar
  24. 24.
    Correa AF, Theisen K, Ferroni M, Maranchie JK, Hrebinko R, Davies BJ, Gingrich JR (2015) The role of interferon in the management of BCG refractory nonmuscle invasive bladder cancer. Adv Urol 2015:656918. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Shepherd AR, Shepherd E, Brook NR (2017) Intravesical Bacillus Calmette-Guerin with interferon-alpha versus intravesical Bacillus Calmette-Guerin for treating non-muscle-invasive bladder cancer. Cochrane Database Syst Rev 3:Cd012112. CrossRefPubMedGoogle Scholar
  26. 26.
    Belldegrun AS, Franklin JR, O’Donnell MA, Gomella LG, Klein E, Neri R, Nseyo UO, Ratliff TL, Williams RD (1998) Superficial bladder cancer: the role of interferon-alpha. J Urol 159(6):1793–1801CrossRefGoogle Scholar
  27. 27.
    Kaji EH, Leiden JM (2001) Gene and stem cell therapies. JAMA 285(5):545–550CrossRefGoogle Scholar
  28. 28.
    Walther W, Schlag PM (2013) Current status of gene therapy for cancer. Curr Opin Oncol 25(6):659–664. CrossRefPubMedGoogle Scholar
  29. 29.
    Rosenberg SA, Aebersold P, Cornetta K, Kasid A, Morgan RA, Moen R, Karson EM, Lotze MT, Yang JC, Topalian SL et al (1990) Gene transfer into humans–immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med 323(9):570–578. CrossRefPubMedGoogle Scholar
  30. 30.
    Wirth T, Parker N, Yla-Herttuala S (2013) History of gene therapy. Gene 525(2):162–169. CrossRefPubMedGoogle Scholar
  31. 31.
    Wysocki PJ, Karczewska-Dzionk A, Mackiewicz-Wysocka M, Mackiewicz A (2004) Human cancer gene therapy with cytokine gene-modified cells. Expert Opin Biol Ther 4(10):1595–1607. CrossRefPubMedGoogle Scholar
  32. 32.
    Baldo BA (2014) Side effects of cytokines approved for therapy. Drug Saf 37(11):921–943. CrossRefPubMedGoogle Scholar
  33. 33.
    Jonasch E, Haluska FG (2001) Interferon in oncological practice: review of interferon biology, clinical applications, and toxicities. Oncologist 6(1):34–55CrossRefGoogle Scholar
  34. 34.
    Bass C, Cabrera G, Elgavish A, Robert B, Siegal GP, Anderson SC, Maneval DC, Curiel DT (1995) Recombinant adenovirus-mediated gene transfer to genitourinary epithelium in vitro and in vivo. Cancer Gene Ther 2(2):97–104PubMedGoogle Scholar
  35. 35.
    Klingler CH (2016) Glycosaminoglycans: how much do we know about their role in the bladder? Urologia 83(Suppl 1):11–14. CrossRefPubMedGoogle Scholar
  36. 36.
    Engler H, Anderson SC, Machemer TR, Philopena JM, Connor RJ, Wen SF, Maneval DC (1999) Ethanol improves adenovirus-mediated gene transfer and expression to the bladder epithelium of rodents. Urology 53(5):1049–1053CrossRefGoogle Scholar
  37. 37.
    Connor RJ, Engler H, Machemer T, Philopena JM, Horn MT, Sutjipto S, Maneval DC, Youngster S, Chan TM, Bausch J, McAuliffe JP, Hindsgaul O, Nagabhushan TL (2001) Identification of polyamides that enhance adenovirus-mediated gene expression in the urothelium. Gene Ther 8(1):41–48. CrossRefPubMedGoogle Scholar
  38. 38.
    Yamashita M, Rosser CJ, Zhou JH, Zhang XQ, Connor RJ, Engler H, Maneval DC, Karashima T, Czerniak BA, Dinney CP, Benedict WF (2002) Syn3 provides high levels of intravesical adenoviral-mediated gene transfer for gene therapy of genetically altered urothelium and superficial bladder cancer. Cancer Gene Ther 9(8):687–691. CrossRefPubMedGoogle Scholar
  39. 39.
    Iqbal Ahmed CM, Johnson DE, Demers GW, Engler H, Howe JA, Wills KN, Wen SF, Shinoda J, Beltran J, Nodelman M, Machemer T, Maneval DC, Nagabhushan TL, Sugarman BJ (2001) Interferon alpha2b gene delivery using adenoviral vector causes inhibition of tumor growth in xenograft models from a variety of cancers. Cancer Gene Ther 8(10):788–795. CrossRefPubMedGoogle Scholar
  40. 40.
    Benedict WF, Tao Z, Kim CS, Zhang X, Zhou JH, Adam L, McConkey DJ, Papageorgiou A, Munsell M, Philopena J, Engler H, Demers W, Maneval DC, Dinney CP, Connor RJ (2004) Intravesical Ad-IFNalpha causes marked regression of human bladder cancer growing orthotopically in nude mice and overcomes resistance to IFN-alpha protein. Mol Ther J Am Soc Gene Ther 10(3):525–532. CrossRefGoogle Scholar
  41. 41.
    Izawa JI, Sweeney P, Perrotte P, Kedar D, Dong Z, Slaton JW, Karashima T, Inoue K, Benedict WF, Dinney CP (2002) Inhibition of tumorigenicity and metastasis of human bladder cancer growing in athymic mice by interferon-beta gene therapy results partially from various antiangiogenic effects including endothelial cell apoptosis. Clin Cancer Res 8(4):1258–1270PubMedGoogle Scholar
  42. 42.
    Benedict WF, Fisher M, Zhang XQ, Yang Z, Munsell MF, Dinney CN (2014) Use of monitoring levels of soluble forms of cytokeratin 18 in the urine of patients with superficial bladder cancer following intravesical Ad-IFNalpha/Syn3 treatment in a phase l study. Cancer Gene Ther 21(3):91–94. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Zhang X, Dong L, Chapman E, Benedict WF (2008) Conditioned medium from Ad-IFN-alpha-infected bladder cancer and normal urothelial cells is cytotoxic to cancer cells but not normal cells: further evidence for a strong bystander effect. Cancer Gene Ther 15(12):817–822. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Zhang X, Yang Z, Dong L, Papageorgiou A, McConkey DJ, Benedict WF (2007) Adenoviral-mediated interferon alpha overcomes resistance to the interferon protein in various cancer types and has marked bystander effects. Cancer Gene Ther 14(3):241–250. CrossRefPubMedGoogle Scholar
  45. 45.
    Connor RJ, Anderson JM, Machemer T, Maneval DC, Engler H (2005) Sustained intravesical interferon protein exposure is achieved using an adenoviral-mediated gene delivery system: a study in rats evaluating dosing regimens. Urology 66(1):224–229. CrossRefPubMedGoogle Scholar
  46. 46.
    Tao Z, Connor RJ, Ashoori F, Dinney CP, Munsell M, Philopena JA, Benedict WF (2006) Efficacy of a single intravesical treatment with Ad-IFN/Syn 3 is dependent on dose and urine IFN concentration obtained: implications for clinical investigation. Cancer Gene Ther 13(2):125–130. CrossRefPubMedGoogle Scholar
  47. 47.
    Vellinga J, Smith JP, Lipiec A, Majhen D, Lemckert A, van Ooij M, Ives P, Yallop C, Custers J, Havenga M (2014) Challenges in manufacturing adenoviral vectors for global vaccine product deployment. Hum Gene Ther 25(4):318–327. CrossRefPubMedGoogle Scholar
  48. 48.
    Dinney CP, Fisher MB, Navai N, O’Donnell MA, Cutler D, Abraham A, Young S, Hutchins B, Caceres M, Kishnani N, Sode G, Cullen C, Zhang G, Grossman HB, Kamat AM, Gonzales M, Kincaid M, Ainslie N, Maneval DC, Wszolek MF, Benedict WF (2013) Phase I trial of intravesical recombinant adenovirus mediated interferon-alpha2b formulated in Syn3 for Bacillus Calmette-Guerin failures in nonmuscle invasive bladder cancer. J Urol 190(3):850–856. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Shore ND, Boorjian SA, Canter DJ, Ogan K, Karsh LI, Downs TM, Gomella LG, Kamat AM, Lotan Y, Svatek RS, Bivalacqua TJ, Grubb RL 3rd, Krupski TL, Lerner SP, Woods ME, Inman BA, Milowsky MI, Boyd A, Treasure FP, Gregory G, Sawutz DG, Yla-Herttuala S, Parker NR, Dinney CPN (2017) Intravesical rAd-IFNalpha/Syn3 for patients with high-grade, Bacillus Calmette-Guerin-refractory or relapsed non-muscle-invasive bladder cancer: a Phase II Randomized Study. J Clin Oncol 35(30):3410–3416. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Dinney CP, Greenberg RE, Steinberg GD (2013) Intravesical valrubicin in patients with bladder carcinoma in situ and contraindication to or failure after bacillus Calmette-Guerin. Urol Oncol 31(8):1635–1642. CrossRefPubMedGoogle Scholar
  51. 51.
    Packiam VT, Lamm DL, Barocas DA, Trainer A, Fand B, Davis RL 3rd, Clark W, Kroeger M, Dumbadze I, Chamie K, Kader AK, Curran D, Gutheil J, Kuan A, Yeung AW, Steinberg GD (2017) An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: interim results. Urol Oncol 45:54. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Jonathan J. Duplisea
    • 1
  • Sharada Mokkapati
    • 1
  • Devin Plote
    • 2
  • Kimberly S. Schluns
    • 3
  • David J. McConkey
    • 4
  • Seppo Yla-Herttuala
    • 5
  • Nigel R. Parker
    • 6
  • Colin P. Dinney
    • 1
  1. 1.Department of UrologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Department of Cancer BiologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  3. 3.Department of ImmunologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  4. 4.James Buchanan Brady Urological Institute, Johns Hopkins Greenberg Bladder Cancer InstituteJohns Hopkins University, School of MedicineBaltimoreUSA
  5. 5.A.I.Virtanen Institute, University of Eastern Finland and Gene Therapy UnitKuopio University HospitalKuopioFinland
  6. 6.Hamesman Ltd.LondonUK

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