Treatment of carcinoma in situ of the urinary bladder with an alpha-emitter immunoconjugate targeting the epidermal growth factor receptor: a pilot study

  • Michael E. Autenrieth
  • Christof Seidl
  • Frank Bruchertseifer
  • Thomas Horn
  • Florian Kurtz
  • Benedikt Feuerecker
  • Calogero D’Alessandria
  • Christian Pfob
  • Stephan Nekolla
  • Christos Apostolidis
  • Saed Mirzadeh
  • Jürgen E. Gschwend
  • Markus Schwaiger
  • Klemens Scheidhauer
  • Alfred Morgenstern
Original Article



Patients with carcinoma in situ (CIS) of the bladder refractory to bacillus Calmette-Guérin (BCG) treatment are usually treated with cystectomy. Therefore, new treatment options with preservation of the urinary bladder are needed. The objective of the study was to investigate the feasibility, safety and efficacy of a novel targeted alpha-emitter immunotherapy for CIS after BCG treatment failure.


A pilot study was conducted in 12 patients (age range 64–86 years, ten men, two women) with biopsy-proven CIS of the bladder refractory to BCG treatment. The patients were treated intravesically with a single instillation (one patient was treated twice) of the alpha-emitter 213Bi coupled to an anti-EGFR antibody (366–821 MBq). The primary aims of the study were to determine the feasibility of treatment with the 213Bi-immunoconjugate and evaluation of adverse effects. Therapeutic efficacy was monitored by histological mapping of the urinary bladder 8 weeks after treatment and at different time points thereafter.


The study proved that intravesical instillation of the 213Bi-immunoconjugate targeting EGFR is feasible. No adverse effects were observed and all blood and urine parameters determined remained in their normal ranges. Therapeutic efficacy was considered satisfactory, in that three of the 12 patients showed no signs of CIS 44, 30 and 3 months after treatment.


Intravesical instillation of 213Bi-anti-EGFR monoclonal antibody was well tolerated and showed therapeutic efficacy. Repeated instillation and/or instillation of higher activities of the 213Bi-immunoconjugate might lead to better therapeutic outcomes. A phase I clinical trial is planned.


Alpha-emitter 213Bi 225Ac/213Bi generator Targeted therapy Bladder cancer Feasibility Adverse effects Therapeutic efficacy 



We owe special thanks to Reingard Senekowitsch-Schmidtke who introduced treatment of bladder cancer xenografts with 213Bi-anti-EGFR immunoconjugates to the scientific community. The authors are indebted for provision of parts of the 225Ac/213Bi used in this study to the Isotope Development and Production for Research and Applications Program, Office of Nuclear Physics, U.S. Department of Energy.


This study was not funded.

Compliance with ethical standards

Conflicts of interest


Ethical approval

The study was approved by the local Ethics Committee.

Informed consent

Informed consent was obtained from all patients included in the study.


  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.CrossRefPubMedGoogle Scholar
  2. 2.
    Kates M, Date A, Yoshida T, Afzal U, Kanvinde P, Babu T, et al. Preclinical evaluation of intravesical cisplatin nanoparticles for non-muscle-invasive bladder cancer. Clin Cancer Res. 2017;23:6592–601.CrossRefPubMedGoogle Scholar
  3. 3.
    Veeratterapillay R, Heer R, Johnson MI, Persad R, Bach C. High-risk non-muscle-invasive bladder cancer-therapy options during intravesical BCG shortage. Curr Urol Rep. 2016;17:68.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    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
  5. 5.
    Gofrit ON, Pode D, Pizov G, Zorn KC, Katz R, Duvdevani M, et al. The natural history of bladder carcinoma in situ after initial response to bacillus Calmette-Gúerin immunotherapy. Urol Oncol. 2009;27:258–62.CrossRefPubMedGoogle Scholar
  6. 6.
    Steinberg RL, Thomas LJ, O'Donnell MA. Bacillus Calmette-Guérin (BCG) treatment failures in non-muscle invasive bladder cancer: what truly constitutes unresponsive disease. Bladder Cancer. 2015;1:105–16.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Hassan JM, Cookson MS, Smith JA Jr, Johnson DL, Chang SS. Outcomes in patients with pathological carcinoma in situ only disease at radical cystectomy. J Urol. 2004;172:882–4.CrossRefPubMedGoogle Scholar
  8. 8.
    Steinberg RL, Thomas LJ, Nepple KG. Intravesical and alternative bladder-preservation therapies in the management of non-muscle-invasive bladder cancer unresponsive to bacillus Calmette-Guérin. Urol Oncol. 2016;34:279–89.CrossRefPubMedGoogle Scholar
  9. 9.
    Morales A. BCG: a throwback from the stone age of vaccines opened the path for bladder cancer immunotherapy. Can J Urol. 2017;24:8788–93.PubMedGoogle Scholar
  10. 10.
    Cardillo MR, Castagna G, Memeo L, De Bernardinis E, Di Silverio F. Epidermal growth factor receptor, MUC-1 and MUC-2 in bladder cancer. J Exp Clin Cancer Res. 2000;19:225–33.PubMedGoogle Scholar
  11. 11.
    Rotterud R, Nesland JM, Berner A, Fossa SD. Expression of epidermal growth factor receptor family in normal and malignant urothelium. BJU Int. 2005;95:1344–50.CrossRefPubMedGoogle Scholar
  12. 12.
    Seidl C. Radioimmunotherapy with α-particle-emitting radionuclides. Immunotherapy. 2014;6:431–58.CrossRefPubMedGoogle Scholar
  13. 13.
    Pfost B, Seidl C, Autenrieth M, Saur D, Bruchertseifer F, Morgenstern A, et al. Intravesical alpha-radioimmunotherapy with 213Bi-anti-EGFR-mAb defeats human bladder carcinoma in xenografted nude mice. J Nucl Med. 2009;50:1700–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Fazel J, Rötzer S, Seidl C, Feuerecker B, Autenrieth M, Weirich G, et al. Fractionated intravesical radioimmunotherapy with 213Bi-anti-EGFR-MAb is effective without toxic side-effects in a nude mouse model of advanced human bladder carcinoma. Cancer Biol Ther. 2015;16:1526–34.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Nikula TK, Curcio MJ, Brechbiel MW, Gansow OA, Finn RD, Scheinberg DA. A rapid, single vessel method for preparation of clinical grade ligand conjugated monoclonal antibodies. Nucl Med Biol. 1995;22:387–90.CrossRefPubMedGoogle Scholar
  16. 16.
    Stabin M. Nuclear medicine dosimetry. Phys Med Biol. 2006;51:R187–202.CrossRefPubMedGoogle Scholar
  17. 17.
    Chou R, Selph S, Buckley DI, Fu R, Griffin JC, Grusing S, et al. Intravesical therapy for the treatment of nonmuscle invasive bladder cancer: a systematic review and meta-analysis. J Urol. 2017;197:1189–99.CrossRefPubMedGoogle Scholar
  18. 18.
    Shore ND, Boorjian SA, Canter DJ, Ogan K, Karsh LI, Downs TM, et al. Intravesical rAd-IFNα/Syn3 for patients with high-grade, bacillus Calmette-Guerin (BCG) refractory or relapsed non-muscle invasive bladder cancer: a phase II randomized study. J Clin Oncol. 2017;35:3410–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Nedrow JR, Josefsson A, Park S, Bäck T, Hobbs RF, Brayton C, et al. Pharmacokinetics, microscale distribution, and dosimetry of alpha-emitter-labeled anti-PD-L1 antibodies in an immune competent transgenic breast cancer model. EJNMMI Res. 2017;7:57.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Bellmunt J, Powles T, Vogelzang NJ. A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: the future is now. Cancer Treat Rev. 2017;54:58–67.CrossRefPubMedGoogle Scholar
  21. 21.
    Cordier D, Krolicki L, Morgenstern A, Merlo A. Targeted radiolabeled compounds in glioma therapy. Semin Nucl Med. 2016;46:243–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Cederkrantz E, Andersson H, Bernhardt P, Bäck T, Hultborn R, Jacobsson L, et al. Absorbed doses and risk estimates of 211At-MX35 F(ab')2 in intraperitoneal therapy of ovarian cancer patients. Int J Radiat Oncol Biol Phys. 2015;93:569–76.CrossRefPubMedGoogle Scholar
  23. 23.
    Meredith RF, Torgue JJ, Rozgaja TA, Banaga EP, Bunch PW, Alvarez RD, et al. Safety and outcome measures of first-in-human intraperitoneal α-radioimmunotherapy with 212Pb-TCMC-trastuzumab. Am J Clin Oncol. 2016. PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Kratochwil C, Schmidt K, Afshar-Oromieh A, Bruchertseifer F, Rathke H, Morgenstern A, et al. Targeted alpha therapy of mCRPC: dosimetry estimate of 213Bismuth-PSMA-617. Eur J Nucl Med Mol Imaging. 2018;45:31–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Kratochwil C, Giesel FL, Bruchertseifer F, Mier W, Apostolidis C, Boll R, et al. 213Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience. Eur J Nucl Med Mol Imaging. 2014;41:2106–19.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Jurcic JG, Rosenblat TL. Targeted alpha-particle immunotherapy for acute myeloid leukemia. Am Soc Clin Oncol Educ Book. 2014:e126–31.Google Scholar
  27. 27.
    Meredith R, Wessels B, Knox S. Risks to normal tissues from radionuclide therapy. Semin Nucl Med. 2008;38:347–57.CrossRefPubMedGoogle Scholar
  28. 28.
    Lim S, Koh MJ, Jeong HJ, Cho NH, Choi YD, Cho do Y, et al. Fibroblast growth factor receptor 1 overexpression is associated with poor survival in patients with resected muscle invasive urothelial carcinoma. Yonsei Med J. 2016;57:831–9.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Tomlinson DC, Baldo O, Harnden P, Knowles MA. FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. J Pathol. 2007;213:91–8.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Inoue M, Koga F, Yoshida S, Tamura T, Fujii Y, Ito E, et al. Significance of ERBB2 overexpression in therapeutic resistance and cancer-specific survival in muscle-invasive bladder cancer patients treated with chemoradiation-based selective bladder-sparing approach. Int J Radiat Oncol Biol Phys. 2014;90:303–11.CrossRefPubMedGoogle Scholar
  31. 31.
    Li C, Yang Z, Du Y, Tang H, Chen J, Hu D, et al. BCMab1, a monoclonal antibody against aberrantly glycosylated integrin α3β1, has potent antitumor activity of bladder cancer in vivo. Clin Cancer Res. 2014;20:4001–13.CrossRefPubMedGoogle Scholar
  32. 32.
    Inman BA, Longo TA, Ramalingam S, Harrison MR. Atezolizumab: a PD-L1-blocking antibody for bladder cancer. Clin Cancer Res. 2017;23:1886–90.CrossRefPubMedGoogle Scholar
  33. 33.
    Sharabi AB, Lim M, DeWeese TL, Drake CG. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol. 2015;16:e498–509.CrossRefPubMedGoogle Scholar
  34. 34.
    Gorin JB, Ménager J, Gouard S, Maurel C, Guilloux Y, Faivre-Chauvet A, et al. Antitumor immunity induced after α irradiation. Neoplasia. 2014;16:319–28.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Ménager J, Gorin JB, Maurel C, Drujont L, Gouard S, Louvet C, et al. Combining α-radioimmunotherapy and adoptive T cell therapy to potentiate tumor destruction. PLoS One. 2015;10:e0130249.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Michael E. Autenrieth
    • 1
  • Christof Seidl
    • 2
    • 3
  • Frank Bruchertseifer
    • 4
  • Thomas Horn
    • 1
  • Florian Kurtz
    • 1
  • Benedikt Feuerecker
    • 3
  • Calogero D’Alessandria
    • 3
  • Christian Pfob
    • 3
  • Stephan Nekolla
    • 3
  • Christos Apostolidis
    • 4
  • Saed Mirzadeh
    • 5
  • Jürgen E. Gschwend
    • 1
  • Markus Schwaiger
    • 3
  • Klemens Scheidhauer
    • 3
  • Alfred Morgenstern
    • 4
  1. 1.Department of UrologyTechnische Universität MünchenMunichGermany
  2. 2.Department of Obstetrics and GynecologyTechnische Universität MünchenMunichGermany
  3. 3.Department of Nuclear MedicineTechnische Universität MünchenMunichGermany
  4. 4.European Commission, Joint Research Centre, Directorate for Nuclear Safety and SecurityKarlsruheGermany
  5. 5.Nuclear Security and Isotope Technology DivisionOak Ridge National LaboratoryOak RidgeUSA

Personalised recommendations