Skip to main content
SpringerLink
Log in

Experimentelle Therapie des Hodgkin-Lymphoms

Experimental therapy for Hodgkin lymphoma

  • Leitthema
  • Published:
Der Onkologe Aims and scope

Zusammenfassung

Die hohen Heilungsraten von 85–95% in allen Stadien des Hodgkin-Lymphoms (HL) werden durch therapieassoziierte Komplikationen bedroht. So versterben Lanzeitüberlebende häufiger an Spättoxizitäten als an einem Rezidiv der Erkrankung. Es erscheint daher notwendig, neue, individualisierte Behandlungskonzepte zu entwickeln, die sich an der Biologie der Erkrankung orientieren. An erster Stelle steht die Definition von Risikogruppen, die eine schlechte Prognose haben und möglicherweise von einer weiteren initialen Therapieeskalation profitieren würden und von Risikogruppen, die eine gute Prognose haben und somit evtl. weniger aggressiv behandelt werden sollten. Biologische Faktoren (histologische Kriterien, serologische Marker oder genetische Polymorphismen) könnten in Kombination mit etablierten klinischen Faktoren die Basis eines neuen Risikoscores bilden. An zweiter Stelle steht die Entwicklung neuer Therapiemodalitäten, die gezielt spezifische molekulare Charakteristika des HL berücksichtigen. Dazu zählen immuntherapeutische Ansätze (Antikörper und zelluläre Vakzine) sowie niedrig molekulare Substanzen oder Antisense-Moleküle, die den proproliferativen und antiapoptotischen Phänotyp der Hodgkin- und Reed-Sternberg-Zellen auf molekularer Ebene angreifen. Bisherige klinische Phase-I/II-Studien zeigen allerdings lediglich einen geringen Effekt der genannten experimentellen Strategien, sodass weitere Entwicklungen unter Berücksichtigung individueller Risikofaktoren notwendig erscheinen.

Abstract

Although 85–95% of Hodgkin Lymphoma (HL) patients can be cured for all stages of the disease, high cure rates are threatened by acute and chronic therapy associated toxicities. Long term survivors of HL are more likely to die from late toxicities than from HL itself. It therefore seems to be necessary to develop novel biologically based therapies for HL. First, it is important to define selected risk groups in order to differentiate between good risk patients who might benefit from a de-escalation of therapy and high risk patients who could receive escalated treatment. Biological factors such as histological markers, serological factors or genomic polymorphisms in combination with established clinical risk factors might be the basis for these novel risk scores in the future. Second, it is crucial to identify transforming mechanisms in HL in order to develop novel therapeutic modalities that specifically target these events. Immunotherapeutic approaches (such as antibodies or cellular vaccines) and small molecules or antisense molecules might be suitable for targeting the pro-proliferative and anti-apoptotic phenotype of Hodgkin and Reed-Sternberg cells. Unfortunately, experimental phase I/II trials have so far showed only little clinical effect in relapsed HL patients. It therefore seems to be necessary to develop novel therapeutic strategies for HL patients based on the molecular characteristics of the malignant cells and individual risk factors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2
Abb. 3

Literatur

  1. Diehl V, Thomas RK, Re D (2004) Part II: Hodgkin‘s lymphoma-diagnosis and treatment. Lancet Oncol 5:19–26

    Google Scholar 

  2. Aleman BM, van den Belt-Dusebout AW, Klokman WJ, Van’t Veer MB, Bartelink H, van Leeuwen FE (2003) Long-term cause-specific mortality of patients treated for Hodgkin’s disease. J Clin Oncol 21:3431–3439

    Google Scholar 

  3. Hasenclever D, Diehl V (1998) A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med 339:1506–1514

    Google Scholar 

  4. Paik S, Shak S, Tang G et al. (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817–2826

    Google Scholar 

  5. Dave SS, Wright G, Tan B et al. (2004) Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 351:2159–2169

    Google Scholar 

  6. Garcia JF, Camacho FI, Morente M et al. (2003) Hodgkin and Reed-Sternberg cells harbor alterations in the major tumor suppressor pathways and cell-cycle checkpoints: analyses using tissue microarrays. Blood 101:681–689

    Google Scholar 

  7. Bohlen H, Kessler M, Sextro M, Diehl V, Tesch H (2000) Poor clinical outcome of patients with Hodgkin’s disease and elevated interleukin-10 serum levels. Clinical significance of interleukin-10 serum levels for Hodgkin’s disease. Ann Hematol 79:110–113

    Google Scholar 

  8. Hohaus S, Massini G, D’Alo‘ F, Guidi F, Putzulu R, Scardocci A, Rabi A, Di Febo AL, Voso MT, Leone G (2003) Association between glutathione S-transferase genotypes and Hodgkin’s lymphoma risk and prognosis. Clin Cancer Res 9:3435–3440

    Google Scholar 

  9. Thomas RK, Re D, Wolf J, Diehl V (2004) Part I: Hodgkin’s lymphoma — molecular biology of Hodgkin and Reed-Sternberg cells. Lancet Oncol 5:11–18

    Google Scholar 

  10. Re D, Hofmann A, Wolf J et al. (2000) Cultivated H-RS cells are resistant to CD95L-mediated apoptosis despite expression of wild-type CD95. Experimental Hematology 28:31–35

    Google Scholar 

  11. Thomas RK, Kallenborn A, Wickenhauser C et al. (2002) Constitutive expression of c-FLIP in Hodgkin and Reed-Sternberg cells. Am J Pathol 160:1521–1528

    Google Scholar 

  12. Mathas S, Lietz A, Anagnostopoulos I et al. (2004) c-FLIP mediates resistance of Hodgkin/Reed-Sternberg cells to death receptor-induced apoptosis. J Exp Med 199:1041–1052

    Google Scholar 

  13. Kashkar H, Haefs C, Shin H et al. (2003) XIAP-mediated caspase inhibition in Hodgkin’s lymphoma-derived B cells. J Exp Med 198:341–347

    Google Scholar 

  14. Renne C, Willenbrock K, Kuppers R, Hansmann ML, Brauninger A (2005) Autocrine- and paracrine-activated receptor tyrosine kinases in classic Hodgkin lymphoma. Blood 105:4051–4059

    Google Scholar 

  15. Kelly WK, Richon VM, O’Connor O et al. (2003) Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin Cancer Res 9:3578–3588

    Google Scholar 

  16. Boll B, Hansen H, Heuck F, Reiners K, Borchmann P, Rothe A, Engert A, Pogge von Strandmann E (2005) The fully human anti-CD30 antibody 5F11 activates NF-kB and sensitizes lymphoma cells to bortezomib-induced apoptosis. Blood (published 5 May 2005)

  17. Schwab U, Stein H, Gerdes J, Lemke H, Kirchner H, Schaadt M, Diehl V (1982) Production of a monoclonal antibody specific for Hodgkin and Sternberg-Reed cells of Hodgkin’s disease and a subset of normal lymphoid cells. Nature 299:65–67

    Google Scholar 

  18. Engert A, Burrows F, Jung W, Tazzari PL, Stein H, Pfreundschuh M, Diehl V, Thorpe P (1990) Evaluation of ricin A chain-containing immunotoxins directed against the CD30 antigen as potential reagents for the treatment of Hodgkin’s disease. Cancer Res 50:84–88

    Google Scholar 

  19. Schnell R, Linnartz C, Katouzi AA, Schon G, Bohlen H, Horn-Lohrens O, Parwaresch RM, Lange H, Diehl V, Lemke H et al. (1995) Development of new ricin A-chain immunotoxins with potent anti-tumor effects against human Hodgkin cells in vitro and disseminated Hodgkin tumors in SCID mice using high-affinity monoclonal antibodies directed against the CD30 antigen. Int J Cancer 63:238–244

    Google Scholar 

  20. Chiarle R, Podda A, Prolla G, Podack ER, Thorbecke GJ, Inghirami G (1999) CD30 overexpression enhances negative selection in the thymus and mediates programmed cell death via a Bcl-2-sensitive pathway. J Immunol 163:194–205

    Google Scholar 

  21. Wiley SR, Goodwin RG, Smith CA (1996) Reverse signaling via CD30 ligand. J Immunol 157:3635–3639

    Google Scholar 

  22. Horie R, Watanabe T (1998) CD30: expression and function in health and disease. Semin Immunol 10:457–470

    Google Scholar 

  23. Wahl AF, Klussman K, Thompson JD, Chen JH, Francisco LV, Risdon G, Chace DF, Siegall CB, Francisco JA (2002) The anti-CD30 monoclonal antibody SGN-30 promotes growth arrest and DNA fragmentation in vitro and affects antitumor activity in models of Hodgkin’s disease. Cancer Res 62:3736–3742

    Google Scholar 

  24. Bartlett NL, Younes A, Carabasi MA, Espina B, DiPersio JF, Schliebner SD, Siegall C, Sing AP (2002) Phase I Study of SGN-30, a Chimeric Monoclonal Antibody (mAb), in Patients with Refractory or Recurrent CD30 + Hematologic Malignancies. Blood:[1403] Abs

  25. Borchmann P, Treml JF, Hansen H et al. (2003) The human anti-CD30 antibody 5F11 shows in vitro and in vivo activity against malignant lymphoma. Blood 102:3737–3742

    Google Scholar 

  26. Ansell S, Byrd J, Horwitz SM et al. (2003) Phase I/II Study of a Fully Human Anti-CD30 Monoclonal Antibody (MDX-060) in Hodgkin’s Disease (HD) and Anaplastic Large Cell Lymphoma (ALCL). Blood 102:Abs 632

    Google Scholar 

  27. Younes A, Romaguera J, Hagemeister F et al. (2003) A pilot study of rituximab in patients with recurrent, classic Hodgkin disease. Cancer 98:310–314

    Google Scholar 

  28. Rehwald U, Schulz H, Reiser M et al. (2003) Treatment of relapsed CD20+ Hodgkin lymphoma with the monoclonal antibody rituximab is effective and well tolerated: results of a phase 2 trial of the German Hodgkin Lymphoma Study Group. Blood 101:420–424

    Google Scholar 

  29. Ekstrand BC, Lucas JB, Horwitz SM et al. (2003) Rituximab in lymphocyte-predominant Hodgkin disease: results of a phase 2 trial. Blood 101:4285–4289

    Google Scholar 

  30. Bollard CM, Aguilar L, Straathof KC et al. (2004) Cytotoxic T lymphocyte therapy for Epstein-Barr virus+ Hodgkin’s disease. J Exp Med 200:1623–1633

    Google Scholar 

Download references

Interessenkonflikt:

Der korrespondierende Autor versichert, dass keine Verbindungen mit einer Firma, deren Produkt in dem Artikel genannt ist, oder einer Firma, die ein Konkurrenzprodukt vertreibt, bestehen.

Author information

Authors and Affiliations

  1. Klinik I für Innere Medizin, Universitätsklinik Köln

    D. Re & P. Borchmann

  2. The Burnham Institute, John Reed Laboratory, La Jolla, USA

    D. Re

  3. Klinik I für Innere Medizin, Universitätsklinik, Kerpenerstraße 62, 50 924, Köln

    D. Re

Authors
  1. D. Re
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. Borchmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D. Re.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Re, D., Borchmann, P. Experimentelle Therapie des Hodgkin-Lymphoms. Onkologe 11, 968–976 (2005). https://doi.org/10.1007/s00761-005-0924-3

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00761-005-0924-3

Schlüsselwörter

Keywords

Search

Navigation