Zytokintherapie bei malignen Hauterkrankungen und insbesondere beim malignen Melanom

Zusammenfassung

Zytokine sind hormonähnliche Glykoproteine mit para- oder autokriner Wirkung. Zytokine regulieren Immunreaktionen und Entzündungsvorgänge. Ihren Effekt üben Zytokine durch Bindung an spezifische Zellrezeptoren aus, welche eine Signalübertragung in die Zelle und schliesslich den biologischen Effekt bewirken. Die Zytokine können unterteilt werden in Interleukine, Interferone, colony-stimulating Factors, Tumornekrosefaktoren und transforming growth Factor β, wobei in der Dermatologie vor allem Interferon-α, -β, -γ, Interleukin-2, GM-CSF sowie Interleukin-12 zur Anwendung kommen. Nebenwirkungen einer Zytokintherapie bestehen meist aus grippalen Beschwerden, ausserdem kann es zu Leukopenien sowie Leberwerterhöhungen kommen. Die Nebenwirkungen lassen sich durch Paracetamol und Dosisanpassung meist gut angehen. Gewisse Zytokine wie z. B. Interferon-α sind für bestimmte dermatologische Erkrankungen bereits registriert, während andere noch in klinischen Studien erprobt werden. Dieser Artikel beschränkt sich auf die Anwendung bei malignen Hauterkrankungen, wo verbesserte Therapieoptionen dringend nötig wären.

Abstract

Cytokines are glycoproteins similar to hormones with a paracrine or autocrine effect. Cytokines regulate immune reactions and inflammatory processes. They bind to specific cell receptors which then activate a signalling cascade and in the end a biological effect. Cytokines can be divided into interleukins, interferons, colony-stimulating factors, tumor necrosis factors and transforming growth factor β. In dermatology, above all interferon-α, -β, -γ, interleukin-2, GM-CSF and interleukin-12 are used. Side effects of a cytokine therapy include flu-like symptoms, leukopenia and increase of liver enzymes. In most cases these side effects can easily be treated with paracetamol and dose reduction. Some cytokines such as interferon-α are already registered whereas others are applied in clinical trials. This article is limited to cytokine therapy of malignant skin tumors, where better treatment results are needed.

Literatur

• 1 Asadullah K, Döcke W D, Reinke P. et al . Cytokine determination. Diagnostic significance from the clinical and immunological viewpoint.  Dtsch Med Wochenschr. 1997;  122 1424-1431
• 2 Opal S M, Huber C E. Bench-to-bedside review: Toll-like receptors and their role in septic shock.  Crit Care. 2002;  6(2) 125-136
• 3 Lien E, Ingalls R R. Toll-like receptors.  Crit Care Med. 2002;  30 (1 Suppl) S1-11
• 4 Modlin R L. Activation of toll-like receptors by microbial lipoproteins: role in host defense.  J Allergy Clin Immunol. 2001;  108 (4 Suppl) S104-S106
• 5 Endo T A, Masuhara M, Yokouchi M. et al . A new protein containing an SH2 domain that inhibits JAK-kinases.  Nature. 1997;  387 (6636) 921-924
• 6 Heim M H. The Jak-STAT pathway: cytokine signalling from the receptor to the nucleus.  J Recept Signal Transduct Res. 1999;  19 (1-4) 75-120
• 7 Nashan D, Luger T A. Cytokines: current status and prospects in the treatment of skin tumors.  Hautarzt. 2001;  52 (8) 691-696
• 8 Stadler R, Mayer-da-Silva A, Bratzke B. et al . Interferons in dermatology.  J Am Acad Dermatol. 1989;  20 (4) 650-656
• 9 Lillemeier B F, Koster M, Kerr I M. STAT1 from the cell membrane to the DNA.  EMBO J. 2001;  20 (10) 2508-2517
• 10 Jaster R, Tschirch E, Bittorf T. et al . Role of STAT5 in interferon-alpha signal transduction in Ba/F3 cells.  Cell Signal. 1999;  11 (5) 331-335
• 11 Wu A J, Chen Z J, Kann E C. et al . Interferon-gamma-induced JAK2 and STAT1 signalling in a human salivary gland cell line.  J Cell Physiol. 1997;  173 (1) 110-114
• 12 Silvennoinen O, Ihle J N, Schlessinger J. et al . Interferon-induced nuclear signalling by Jak protein tyrosine kinases.  Nature. 1993;  366 (6455) 583-585
• 13 Nashan D, Luger T A. Stand und Perspektiven in der Behandlung von Hauttumoren.  Hautarzt. 2001;  52 (8) 691-696
• 14 Dummer R, Nestle F O, Burg G. Immunotherapy of melanoma.  Dtsch Med Wochenschr. 2000;  125 (41) 1240-1242
• 15 Stadler R, Otte H G, Luger T. et al . Prospective randomized multicenter clinical trial on the use of interferon-2a plus acitretin versus interferon-2a plus PUVA in patients with cutaneous T-cell lymphoma stages I and II.  Blood. 1998;  92 (10) 3578-3581
• 16 Urosevic M, Dummer R. Immunotherapy for nonmelanoma skin cancer: does it have a future?.  Cancer. 2002;  94 (2) 477-485
• 17 Lippmann S M, Parkinson D R, Itri L M. et al . 13-cis-retinoid acid and interferon-alpha2a: effective combination therapy for advanced squamous cell carcinoma of the skin.  J Nat Cancer Ins. 1992;  84 235-241
• 18 Chimenti S, Peris K, Di Cristofaro S. et al . Use of recombinant interferon alfa-2b in the treatment of basal cell carcinoma.  Dermatology. 1995;  190 214-217
• 19 Ulrich L, Krause M, Brachmann A. et al . Successful treatment of angiosarkoma of the scalp by intralesional cytokine therapy and surface irradiation.  J Eur Acad Dermatol Venereol. 2000;  14 (5) 412-415
• 20 Kageshita T, Mizuno M, Ono T. et al . Growth inhibition of human malignant melanoma transfect with human interferon-beta gene by means of cationic liposomes.  Melanoma Res. 2001;  11 (4) 337-342
• 21 Nagatani T, Okazawa H, Kambara T. et al . Effect of natural interferon-beta on the growth of melanoma cell lines.  Melanoma Res. 1998;  8 (4) 295-299
• 22 Fierlbeck G, d’Hoedt B, Stroebel W. et al . Intralesional therapy of melanoma metastases with recombinant interferon-beta.  Hautarzt. 1992;  43 (1) 16-21
• 23 Kowalzick L, Mensing H, Weyer U. et al . Bowenoid actinic keratosis: therapy with intralesional injection of recombinant beta-interferon.  Hautarzt. 1992;  43 (6) 373-375
• 24 Mahrle G, Schulze H J. Recombinant interferon-gamma (rIFN-gamma) in dermatology.  J Invest Dermatol. 1990;  95 (6 Suppl) 132S-137S
• 25 Gross G, Roussaki A, Papendick U. Efficacy of interferons on bowenoid papulosis and other precancerous lesions.  J Invest Dermatol. 1990;  95 (6 Suppl) 152S-157S
• 26 Edwards L, Whiting D, Rogers D. et al . The effect of intralesional interferon gamma on basal cell carcinomas.  J Am Acad Dermatol. 1990;  22 (3) 496-500
• 27 Stadler R, Mayer-da-Silva A, Bratzke B. et al . Interferons in dermatology.  J Am Acad Dermatol. 1989;  20 (4) 650-656
• 28 Lejeune F J, Kroon B B, DiFilippo F. et al . Isolated limb perfusion: the European experience.  Surg Oncol Clin N Am. 2001;  10 (4) 821-832 ix
• 29 Dummer R, Garbe C, Thompson J A. et al .A randomized dose escalation study evaluating the safety, tolerability and efficacy of peginterferon alfa-2a (40KD) in patients with metastatic malignant melanoma. ASCO-Abstract. 
• 30 Dummer R, Welters H, Keilholz U. et al . Interleukin 2: immunologic background and clinical use in tumor therapy.  Hautarzt. 1990;  41 (2) 53-55
• 31 Nelson B H, Lord J D, Greenberg P D. Cytoplasmic domains of the interleukin-2 receptor beta and gamma chains mediate the signal for T-cell proliferation.  Nature. 1994;  369 (6478) 333-336
• 32 Williamson P, Merida I, Gaulton G. Protein and lipid kinase activation cascades in interleukin-2 receptor signalling.  Semin Immunol. 1993;  5 (5) 337-344
• 33 Liu K D, Greene W C, Goldsmith M A. The alpha chain of the IL-2 receptor determines the species specifity of high-affinity IL-2 binding.  Cytokine. 1996;  8 (8) 613-621
• 34 Minami Y, Kono T, Miyazaki T. et al . The IL-2 receptor complex: its structure, function, and target genes.  Annu Rev Immunol. 1993;  11 245-268
• 35 Witthuhn B A, Silvennoinen O, Miura O. et al . Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells.  Nature. 1994;  370 (6485) 153-157
• 36 Nakamura Y, Russel S M, Mess S A. et al . Heterodimerization of the IL-2 receptor beta- and gamma-chain cytoplasmic domains is required for signalling.  Nature. 1994;  369 (6478) 330-333
• 37 Demoulin J B, Renauld J C. Signalling by cytokines interacting with the interleukin-2 receptor gamma chain.  Cytokines Cell Mol Ther. 1998;  4 (4) 243-256
• 38 Tsujino S, Miyazaki T, Kawahara A. et al . Critical role of the membrane-proximal, proline-rich motif of the interleukin-2 receptor gamma chain in the Jak3-independent signal transduction.  Genes cells. 1999;  4 (6) 363-373
• 39 Kaplan B, Moy R L. Effect of perilesional injections of PEG-interleukin-2 on basal cell carcinoma.  Dermatol Surg. 2000;  26 (11) 1037-1040
• 40 Rochlitz C, Dreno B, Jantscheff P. et al . Immunotherapy of metastatic melanoma by intratumoral injections of Vero cells producing human IL-2: phase II randomized study comparing two dose levels.  Cancer Gene Ther. 2002;  9 (3) 289-295
• 41 Belli F, Arienti F, Sule-Suso J. et al . Active immunization of metastatic melanoma patients with interleukin-2-transduced allogeneic melanoma cells: evaluation of efficacy and tolerability.  Cancer Immunol Immunother. 1997;  45 (2) 119
• 42 Spitler L E. Adjuvant therapy of melanoma.  Oncology (Huntingt). 2002;  16 (1 Suppl 1) 40-48
• 43 Tu J, Karasavvas N, Heaney M L. et al . Molecular characterization of a granulocyte macrophage-colony-stimulating factor receptor alpha subunit-associated protein, GRAP.  Blood. 2000;  96 (3) 794-799
• 44 Scott C L, Begley C G. The beta common chain (beta c) of the granulocyte macrophage-colony stimulating facto, interleukin-3 and interleukin-5 receptors.  Int J Biochem Cell Biol. 1999;  31 (10) 1011-1015
• 45 Dijkers P F, van Dijk T B, de Groot R P. et al . Regulation and function of protein kinase B and MAP kinase activation by the IL-5/GM-CSF/IL-3 receptor.  Oncogene. 1999;  18 (22) 3334-3342
• 46 Nicola N A, Smith A, Robb L. et al . The structural basis of the biological actions of the GM-CSF receptor.  Ciba Found Symp. 1997;  204 19-27; discussion 27-32
• 47 Quelle F W, Sato N, Witthuhn B A. et al . JAK2 associates with the beta c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region.  Mol Cell Biol. 1994;  14 (7) 4335-4341
• 48 Hoeller C, Jansen B, Heere-Ress E. et al . Perilesional injection of r-GM-CSF in patients with cutaneous melanoma metastases.  J Invest Dermatol. 2001;  117 (2) 371-374
• 49 Mahvi D M, Shi F S, Yang N S. et al . Immunization by particle-mediated transfer of the granulocyte-macrophage colony-stimulating factor gene into autologous tumor cells in melanoma or sarcoma patients: report of a phase I/IIB study.  Hum Gene Ther. 2002;  13 (14) 1711-1721
• 50 Dranoff G. GM-CSF-based cancer vaccines.  Immunol Rev. 2002;  188 (1) 147-154
• 51 Hunger R E, Brand C U, Streit M. et al . Successful induction of immune responses against mutant ras in melanoma patients using intradermal injection of peptide and GM-CSF as adjuvant.  Exp Dermatol. 2001;  10 (3) 161-167
• 52 Yue F Y, Geertsen R, Hemmi S. et al . IL-12 directly up-regulates the expression of HLA class I, HLA class II and ICAM-1 on human melanoma cells: a mechanism for its antitumor activity?.  Eur J Immunol. 1999;  29 (6) 1762-1773
• 53 van Rietschoten J G, Smits H H, Westland R. et al . Genomic organization of the human interleukin-12 receptor beta2-chain gene.  Immunogenetics. 2000;  51 (1) 30-36
• 54 Nashan D, Luger T A. Cytokines: current status and prospects in the treatment of skin tumors.  Hautarzt. 2001;  52 (8) 691-696
• 55 Rook A H, Zaki M H, Wysocka M. et al . The role for interleukin-12 therapy of cutaneous T cell lymphoma.  Ann N Y Acad Sci. 2001;  941 177-184
• 56 Rook A H, Wood G S, Yoo E K. et al . Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion regression and cytotoxic T-cell responses.  Blood. 1999;  94 (3) 902-908
• 57 Yue F Y, Cao L, Hemmi S. et al . Upregulation of interleukin-12 receptor on peripheral blood mononuclear cells and HLA class I, HLA class II or ICAM-1 on melanoma cells by B7.1 and interleukin-12: a mechanism for immunostimulatory impact of melanoma cells adenoviral transfected with B7.1 and IL12?.  Melanoma Res. 2000;  10 (4) 313-322
• 58 Gibson S J, Lindh J M, Riter T R. et al . Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and resiquimod.  Cell Immunol. 2002;  218 (1-2) 74-86
• 59 Stanley M A. Imiquimod and the imidazoquinolones: mechanism of action and therapeutic potential.  Clin Exp Dermatol. 2002;  27 (7) 571-577
• 60 Hengge U R, Benninghoff B, Ruzicka T. et al . Topical immunomodulators - progress towards treating inflammation, infection, and cancer.  Lancet Infect Dis. 2001;  1 (3) 189-198
• 61 Tyring S, Conant M, Marini M. et al . Imiquimod; an international update on therapeutic uses in dermatology.  Int J Dermatol. 2002;  41 (11) 810-816
• 62 Stockfleth E, Meyer T, Benninghoff B. et al . A randomized, double-blind, vehicle-controlled study to assess 5% imiquimod cream for the treatment of multiple actinic keratoses.  Arch Dermatol. 2002;  138 (11) 1498-1502
• 63 Gupta A K, Browne M, Bluhm R. Imiquimod: A Review.  J Cutan Med Surg. 2002;  6 (6) 554-560
• 64 Bong A B, Bonnekoh B, Franke I. et al . Imiquimod, a topical immune response modifier, in the treatment of cutaneous metastases of malignant melanoma.  Dermatology. 2002;  205 (2) 135-138
• 65 Ahmed I, Berth-Jones J. Imiquimod: a novel treatment for lentigo maligna.  Br J Dermatol. 2000;  143 (4) 843-845
• 66 Dummer R, Urosevic M, Kempf W. et al . Imiquimod induces complete clearance of a PUVA resistant plaque in Mycosis fungoides.  Dermatology. 2003;  207 116-118
• 67 Asadullah K, Sterry W, Trefzer U. Cytokine therapy in dermatology.  Exp Dermatol. 2002;  11 (2) 97-106
• 68 Oh C J, Das K M, Gottlieb A B. Treatment with antitumor necrosis factor α (TNF-α) monoclonal antibody dramatically decreases the clinical activity of psoriasis lesions.  J Am Acad Dermatol. 2000;  42 829-830
• 69 Kirby B, Marsland A M, Carmichael A J. et al . Successful treatment of severe recalcitrant psoriasis with combination infliximab and methotrexate.  Clin Exp Dermatol. 2001;  26 27-29
• 70 Chaudhari U, Romano P, Mulcahy L D. et al . Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomised trial.  Lancet. 2001;  357 1842-1847
• 71 Mease P J, Goffe B S, Metz J. et al . Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial.  Lancet. 2000;  356 385-390
• 72 Groenewegen G, Bloem A, De Gast G C. Phase I/II study of sequential chemoimmunotherapy (SCIT) for metastatic melanoma: outpatient treatment with dacarbazine, granulocyte-macrophage colony-stimulating factor, low-dose interleukin-2 and interferon-alpha.  Cancer Immunol Immunother. 2002;  51 (11-12) 630-636
• 73 O’Day S J, Boasberg P D, Piro L. et al . Maintenance biotherapy for metastatic melanoma with interleukin-2 and granulocyte macrophage-colony stimulating factor improves survival for patients responding to induction concurrent biochemotherapy.  Clin Cancer Res. 2002;  8 (9) 2775-2781
• 74 Ridolfi L, Ridolfi R, Ascari-Raccagni A. et al . Intralesional granulocyte-monocyte colony-stimulating factor followed by subcutaneous interleukin-2 in metastatic melanoma: a pilot study in elderly patients.  J Eur Acad Dermatol Venereol. 2001;  15 (3) 218-223
• 75 Fritz T M, Kleinhans M, Nestle F O. et al . Combination treatment with extracorporeal photopheresis, interferon alfa and interleukin-2 in a patient with the Sezary syndrome.  Br J Dermatol. 1999;  140 (6) 1144-1147