Cancer Immunology, Immunotherapy

, Volume 52, Issue 8, pp 481–486 | Cite as

Urinary interleukin-2 may predict clinical outcome of intravesical bacillus Calmette-Guérin immunotherapy for carcinoma in situ of the bladder

  • Etsuya Watanabe
  • Hideyasu Matsuyama
  • Kenji Matsuda
  • Chietaka Ohmi
  • Yasuhide Tei
  • Satoru Yoshihiro
  • Yasukazu Ohmoto
  • Katsusuke Naito
Original Article

Abstract

Purpose

The mechanism by which bacillus Calmette-Guérin (BCG) mediates antitumor activity has not been clearly established. Specific cytokines in the urine after BCG intravesical instillation therapy may serve as a prognostic factor of treatment response. In this study, various urinary cytokines such as interleukin-1β (IL-1β), IL-2, IL-6, IL-8. IL-10, IL-12, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) were measured.

Materials and methods

In total 20 patients were treated with BCG intravesical instillation therapy for carcinoma in situ of the bladder . At the completion of the first and eighth instillations, spontaneously voided urine specimens were collected before BCG instillation, every 2 h until 12 h, and thereafter until 24 h. All specimens were ultrafiltrated using an ADVANTEC UK-10 membrane. The cytokines were measured using ELISA and RIA techniques.

Results

Significantly higher levels of IL-2, IL-6, IL-8, IL-10, IFN-γ, and TNF-α were detected in the eighth instillation as compared to the first instillation (p<0.001). After BCG intravesical instillation therapy, treatment failure occurred in 6 of the 20 patients (30%), including primary failure (persistence of CIS) in 3, and de novo failure (tumor recurrence) in 3 with a median follow-up of 46.9 months. Significantly higher production of IL-2, IL-6, IL-8, IL-10, and TNF-α was observed in the responder group than in the non-responder group (p<0.05). Multivariate analysis revealed IL-2 as an independent prognostic cytokine of responder status.

Conclusions

This study indicates that urinary IL-2 at the eighth instillation of BCG may serve as a valuable prognostic factor of treatment efficacy as well as tumor recurrence after treatment.

Keywords

BCG Cytokines Bladder cancer IL-2 Prognosis 

References

  1. 1.
    Alexandroff AB, Jackson AM, O'Donnell MA, James K (1999) BCG immunotherapy of bladder cancer: 20 years on. Lancet 353:1689PubMedGoogle Scholar
  2. 2.
    Bettex-Galland M, Studer UE, Walz A, Dewald B, Baggiolini M (1991) Neutrophil-activating peptide-1/interleukin-8 detection in human urine during acute bladder inflammation caused by transurethral resection of superficial cancer and bacillus Calmette-Guérin. Eur Urol 19:171PubMedGoogle Scholar
  3. 3.
    Böhle A, Nowc CH, Ulmer AJ, Musehold J, Gedes J, Hofstetter AG, Flad MD (1990) Elevations of cytokines interleukin-1, interleukin-2 and tumor necrosis factor in the urine of patients after intravesical bacillus Calmette-Guérin immunotherapy. J Urol 144:59PubMedGoogle Scholar
  4. 4.
    De Boer EC, De Jong WH, Steerenberg PA (1992) Induction of interleukin-1 (IL-1), IL-2, IL-6, and tumour necrosis factor during intravesical immunotherapy with bacillus Calmette-Guérin in superficial bladder cancer. Cancer Immunol Immunother 34:306PubMedGoogle Scholar
  5. 5.
    De Boer EC, Somogyi L, Ruiter GJ de, Reijke TM de, Kurth KH, Schamhart DH (1997) Role of interleukin-8 in onset of the immune response in intravesical BCG therapy for superficial bladder cancer. Urol Res 25:31PubMedGoogle Scholar
  6. 6.
    De Jong WH, De Boer EC, Van der Meijden AP, Vegt P, Steerenberg PA, Debruyne FM, Ruitenberg EJ (1990) Presence of interleukin-2 in urine of superficial bladder cancer patients after intravesical treatment with bacillus Calmette-Guérin. Cancer Immunol Immunother 31:182PubMedGoogle Scholar
  7. 7.
    De Marco R, Ensor J, Hasday J (1992) Tumour-stimulated release of tumour necrosis factor-alpha by human monocyte derived macrophages. Cell Immunol 140:304PubMedGoogle Scholar
  8. 8.
    De Reijke TM, De Boer EC, Kurth KH. Schamhartm DH (1996) Urinary cytokines during intravesical bacillus Calmette-Guérin therapy for superficial bladder cancer: processing, stability and prognostic value. J Urol 155:477PubMedGoogle Scholar
  9. 9.
    Fleischmann JD, Toossi Z, Ellner JJ, Wentworth DB, Ratliff TL, Imbembo AL (1989) Urinary interleukins in patients receiving intravesical bacillus Calmette-Guérin therapy for superficial bladder cancer. Cancer 64:1447PubMedGoogle Scholar
  10. 10.
    Ikuta Y, Katayama N, Wang L et al. (2002) Presentation of a major histocompatibility complex class 1-binding peptide by monocyte-derived dendritic cells incorporating hydrophobized polysaccharide-truncated HER2 protein complex: implications for a polyvalent immuno-cell therapy. Blood 99:3717CrossRefPubMedGoogle Scholar
  11. 11.
    Jackson AM, Alexandrov AB, Gribben SC, Esuvarnathan K, James K (1993) Expression and shedding of ICAM-1 in bladder cancer and its immunotherapy. Int J Cancer 55:921PubMedGoogle Scholar
  12. 12.
    Jackson AM, Prescott S, Hawkyard SJ, James K, Chisholm G (1993) The immunomodulatory effects of urine from patients with superficial bladder cancer receiving intravesical Evans BCG therapy. Cancer Immunol Immunother 36:25PubMedGoogle Scholar
  13. 13.
    Jackson AM, Alexandroff AB, McIntyre M, Esuvaranathan K, James K, Chisholm GD (1994) Induction of ICAM 1 expression on bladder tumours by BCG immunotherapy. J Clin Pathol 47:309PubMedGoogle Scholar
  14. 14.
    Jackson AM, Alexandrov AB, Prescott S, James K (1995) Production of urinary tumour necrosis factors and soluble tumour necrosis factor receptors in bladder cancer patients after bacillus Calmette-Guérin immunotherapy. Cancer Immunol Immunother 40:119CrossRefPubMedGoogle Scholar
  15. 15.
    Jackson AM, Alexandroff AB, Kelly RW, Skibinska A, Esuvaranathan K, Prescott S, Chisholm GD, James K (1995) Changes in urinary cytokines and soluble intercellular adhesion molecule-1 (ICAM-1) in bladder cancer patients after bacillus Calmette-Guérin (BCG) immunotherapy. Clin Exp Immunol 99:369PubMedGoogle Scholar
  16. 16.
    Jackson AM, Ivshina AV, Senko O et al. (1998) Prognosis of intravesical bacillus Calmette-Guérin therapy for superficial bladder cancer by immunological urinary measurements: statistically weighted syndromes analysis. J Urol 159:1054PubMedGoogle Scholar
  17. 17.
    Kenis G, Teunissen C, Jongh R, Bosmans E, Steinbusch H, Maes M (2002) Stability of interleukin 6, soluble interleukin 6 receptor, interleukin 10 and CC16 in human serum. Cytokine 19:228CrossRefPubMedGoogle Scholar
  18. 18.
    Kurisu H, Matsuyama H, Ohmoto Y, Shimabukuro T, Naito K (1994) Cytokine-mediated antitumor effect of bacillus Calmette-Guérin on tumor cells in vitro. Cancer Immunol Immunother 39:249CrossRefPubMedGoogle Scholar
  19. 19.
    Lamm DL (1992) Long-term results of intravesical therapy for superficial bladder cancer. Urol Clin North Am 19:573PubMedGoogle Scholar
  20. 20.
    Lamm DL, Steg A, Boccon-Gibod L, Morales A, Hanna MG Jr, Pagano F, Alfthan O, Brosman S, Fisher HA, Jakse G (1989) Complications of bacillus Calmette-Guérin immunotherapy: review of 2602 patients and comparison of chemotherapy complications. Prog Clin Biol Res 310:335PubMedGoogle Scholar
  21. 21.
    Morales A, Edinger D, Bruce AW (1976) Intracavity bacillus Calmette Guérin in the treatment of superficial bladder tumours. J Urol 116:180PubMedGoogle Scholar
  22. 22.
    Patard JJ, Saint F, Velotti F, Abbou CC, Chopin DK (1998) Immune response following intravesical bacillus Calmette-Guérin instillations in superficial bladder cancer : a review. Urol Res 26:155CrossRefPubMedGoogle Scholar
  23. 23.
    Prescott S, James K, Hargreave TB (1990) Radioimmunoassay detection of interferon-gamma in urine after intravesical BCG therapy. J Urol 144:1248PubMedGoogle Scholar
  24. 24.
    Prescott S, James K, Hargreave TB, Chisholm GD, Smyth JF (1992) Intravesical Evans strain BCG therapy: quantitative immunohistochemical analysis of the immune response within the bladder wall. J Urol 147:1636PubMedGoogle Scholar
  25. 25.
    Rabinowitz R, Smith DS, Tiemann DD et al. (1997) Urinary interleukin-8/creatinine level as predictor of response to intravesical bacillus Calmette-Guérin therapy in bladder tumor patients. J Urol 158:1728PubMedGoogle Scholar
  26. 26.
    Ratliff TL, Haaf EO, Catalona WJ (1986) Interleukin-2 production during intravesical bacillus Calmette-Guérin therapy for bladder cancer. Clin Immunol Immunopathol 40:375PubMedGoogle Scholar
  27. 27.
    Ratliff TL, Kavoussi LR, Catalona WJ (1988) Role of fibronectin in intravesical BCG therapy for superficial bladder cancer. J Urol 139:410PubMedGoogle Scholar
  28. 28.
    Saint F, Patard JJ, Maille P, Soyeux P, Hoznek A, Salomon L, De la Taille A, Abbou CC, Chopin DK (2001) T helper lymphocyte urinary cytokine profiles in responding and nonresponding patients after 1 and 2 courses of bacillus Calmette-Guérin for superficial bladder cancer. J Urol 166:2142PubMedGoogle Scholar
  29. 29.
    Thalmann GN, Dewald B, Baggliolini M, Studer UE (1997) Interleukin-8 expression in the urine after bacillus Calmette-Guérin therapy: a potential prognostic factor of tumor recurrence and progression. J Urol 158:1340PubMedGoogle Scholar
  30. 30.
    Wang MH, Chen YQ, Gercken J, Ernst M, Böhle A, Flad HD, Ulmer AJ (1993) Specific activation of human peripheral blood gamma/delta+ lymphocytes by sonicated antigens of Mycobacterium tuberculosis: role in vitro in killing human bladder carcinoma cell lines. Scand J Immunol 38:239PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Etsuya Watanabe
    • 1
  • Hideyasu Matsuyama
    • 1
  • Kenji Matsuda
    • 1
  • Chietaka Ohmi
    • 1
  • Yasuhide Tei
    • 1
  • Satoru Yoshihiro
    • 1
  • Yasukazu Ohmoto
    • 2
  • Katsusuke Naito
    • 1
  1. 1.Department of UrologyYamaguchi University School of MedicineYamaguchiJapan
  2. 2.Cellular Technology InstitutesOtsuka Pharmaceutical Co.TokushimaJapan

Personalised recommendations