Medical Oncology

, Volume 13, Issue 3, pp 161–166 | Cite as

Neutralising antibodies to granulocyte-macrophage colony stimulating factor (GM-CSF) in carcinoma patients following GM-CSF combination therapy

  • Peter Ragnhammar
  • Meenu Wadhwa


There is a high risk of developing neutralizing and non-neutralizing antibodies when GM-CSF is used as an immunomodulatory agent in non-immune compromised patients and not in combination with chemotherapy. The presence of neutralizing antibodies may seriously hamper the clinical response of the patients This must be taken into account when designing protocols if the biologic activity of the exogenously administered GM-CSF is not to be impaired and the endogenous production of GM-CSF is not to be inactivated. Assessment of production of neutralising antibodies during cytokine therapy is important for predicting the clinical response to progressive therapy.


GM-CSF antibody production neutralisation clinical effects 


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  1. 1.
    Ratain, M., Golomb, H., Vardiman, J., Yokes, E., Jacobs, R. and Daly, K. (1985) Treatment of hairy cell leukemia with recombinant alpha2 interferon.Blood 65, 644.PubMedGoogle Scholar
  2. 2.
    Huber, C, Flener, R. and Gastl, G. (1985) Interferon-alpha- 2C in the treatment of hairy cell leukemia.Oncology 42 (suppl 1), 7.PubMedCrossRefGoogle Scholar
  3. 3.
    Foon, K., Maluish, A. and Abrams, P. (1986) Recombinant leukocyte A interferon therapy for advanced hairy cell leukemia: therapeutic and immunologic results.Am. J. Med. 80, 351.PubMedCrossRefGoogle Scholar
  4. 4.
    Steis, R.G., Smith, J.W., Urba, W.J., Clark, J.W., Irri, L.M., Evans, L.M., Schoenberger, C. and Longo, D.L. (1988) Resistance to recombinant interferon alfa-2a in hairy-cell leukaemia associated with neutralizing anti-interferon antibodies.N. Engl. J. Med. 318, 1409.PubMedCrossRefGoogle Scholar
  5. 5.
    Steis, R. and Longo, D. (1994) Clinical relevance of recombinant interferon-u2 antibodies in patients with hairy cell leukemia.J. Interferon Res. 14, 207.PubMedGoogle Scholar
  6. 6.
    Antonelli, G., Giannelli, G., Pistello, M., Maggi, F., Vatterom, L., Currenti, M., Del Vecchio, S., Roffi, L., Pastore, G. and Dianzani, F. (1994) Clinical significanceof recombinant interferon-α2 neutralizing antibodies in hepatitis patients.J. Interferon. Res. 14, 211.PubMedGoogle Scholar
  7. 7.
    Oberg, K. (1994) Autoimmunity and antibodies to interferons in patients with carcinoid tumors: clinical consequences.J. Interferon Res. 14, 215.PubMedGoogle Scholar
  8. 8.
    Antonelli, G., Currenti, M., Turriziani, O. and Dianzani, F. 1991) Neutralizing antibodies to interferon-a: relative frequency in patients treated with different interferon preparations.J. Infect. Dis. 163, 882.PubMedGoogle Scholar
  9. 9.
    Rönnblom, L., Tiensuujanson, E. and Peters, A. (1992) Characterization of anti-interferon-a antibodies appearing during recombinant interferon-α2a treatment.Clin. Exp. Immunol. 89, 330.PubMedGoogle Scholar
  10. 10.
    Galton, J.E., Bedford, P. and Scott, J.E. (1989) Antibodies to lymphoblastoid interferon.Lancet ii, 572.CrossRefGoogle Scholar
  11. 11.
    Ragnhammar, P., Friesen, H.-J., Frödin, J.-E., Lefvert, A. K., Hassan, M., Österborg, A. and Mellstedt, H. (1994) Induction of anti-recombinant human granulocyte-macro- phage colony-stimulating factor(Escherichia coli-derived) antibodies and clinical effects in nonimmunocompromised patients.Blood 84, 4078.PubMedGoogle Scholar
  12. 12.
    Dorr, R.T. (1993) Clinical properties of yeast-derived versusEscherichia coli-derived granulocyte-macrophage colony-stimulating factor.Clinical Therapeutics 15, 19.PubMedGoogle Scholar
  13. 13.
    Wong, G.C., Witeck, J.S. and Temple, P.A. (1985) Human GM-CSF: molecular cloning of the complementary DNA and purification of the natural and recombinant proteins.Science 228, 810.PubMedCrossRefGoogle Scholar
  14. 14.
    Canrrell, M.A., Anderson, D. and Cerretti, D.P. (1985) Cloning, sequence and expression of a human granulocyte macrophage colony stimulating factor.Proc. Natl. Acad. Sci. 82, 6250.CrossRefGoogle Scholar
  15. 15.
    Burgess, A.W., Begley, CG., Johnson, G.R., Lopez, A.F., Williamson, DJ., Mermod, J.J., Simpson, R.J., Schmitz, A. and DeLamarter, J.F. (1987) Purification and properties of bacterially synthesized human granulocyte-macrophage colony stimulating factor.Blood 69, 43.PubMedGoogle Scholar
  16. 16.
    Gamble, J.R., Elliott, M.J., Jaipargas, E., Lopez, A.F. and Vadas, M.A. (1989) Regulation of human monocyte adherence by granulocyte-macrophage colony-stimulating factor.Proc. Natl. Acad. Sci. USA 86, 7169.PubMedCrossRefGoogle Scholar
  17. 17.
    Arnaout, M., Wang, E., Clark, S. and Sieff, C. (1986) Human recombinant granulocyte-macrophage colony-stimulating factor increases cell to cell adhesion and surface expression of adhesion promoting glycoproteins on mature granulocytes.J. Clin. Invest. 78, 597.PubMedCrossRefGoogle Scholar
  18. 18.
    Morrissey, P., Bressler, L., Park, L., Alpert, A. and Gillis, S. (1987) Granulocyte-macrophage colony-stimulating factor augments the primary antibody response by enhancing the function of antigen presenting cells.J. Immunol. 139, 1113.PubMedGoogle Scholar
  19. 19.
    Vadas, M., Nicola, N. and Metcalf, D. (1983) Activation of antibody dependent cell mediated cytotoxicity of human neutrophils and eosinophils by separate colony stimulating factors.J. Immunol. 130, 795.PubMedGoogle Scholar
  20. 20.
    Masucci, P., Wersäll, P., Ragnhammar, P. and Mellstedt, H. (1989) Granulocyte-monocyte-colony-stimulating factor augments the cytotoxic capacity of lymphocytes and monocytes in antibody-dependent cellular cytotoxicity.Cancer Immunol. Immunother. 29, 288.PubMedCrossRefGoogle Scholar
  21. 21.
    Hill, A., Redmond, R, Austin, O., Grace, P. and Bouchier-Hayes, D. (1993) Granulocyte-macrophage colony-stimulating factor inhibits tumor growth.Br. J. Surg. 80, 1543.PubMedCrossRefGoogle Scholar
  22. 22.
    Charak, B., Agah, R. and Mazumder, A. (1993) Granulocyte-macrophage colony-stimulating factor-induced antibody-dependent cellular cytotoxicity in bone marrow macrophages: application in bone marrow transplantation.Blood 81, 3474.PubMedGoogle Scholar
  23. 23.
    Hooijberg, E., Sein, J. and van den Berg, P. (1995) Eradication of large human B-cell tumors in nude mice with unconjugated CD20 monoclonal antibodies and interleukin-2.Cancer Res. 55, 2627.PubMedGoogle Scholar
  24. 24.
    Cebon, J., Dempsey, P., Fox, R., Kannourakis, G., Bonnern, E.; Burgess, A. and Morstyn, G. (1988) Pharmacokinetics of human granulocyte-macrophage colony-stimulating factor using a sensitive immunoassay.Blood 72, 1340.PubMedGoogle Scholar
  25. 25.
    Hovgaard, D., Mortensen, B., Schifter, S. and Nissen, N. (1992) Clinical pharmacokinetic studies of a human hae- mopoietic growth factor, GM-CSF.Eur. J. Invest. 22, 45.CrossRefGoogle Scholar
  26. 26.
    Wadhwa, M., Bird, C, Fagerberg, J., Gaines-Das, R., Ragnhammar, P. and Mellstedt, H. (1996) Production of neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in carcinoma patients following GM-CSF combination therapy.Clin. Exp. Immunol. 104, 351.PubMedCrossRefGoogle Scholar
  27. 27.
    Thompson, J.A., Lee, D.J., Kidd, P., Rubin, E., Kaufman, J., Bonnern, E.M. and Fefer, A. (1989) Subcutaneous granulocyte macrophage colony-stimulating factor in patients with myelodysplastic syndrome: Toxicity pharmacokinetics and hematological effects.J. Clin. Oncol. 7, 629.PubMedGoogle Scholar
  28. 28.
    Gribben, J.G., Devereux, S., Thomas, N.S.B., Keim, M., Jones, H.M., Goldstone, A.H. and Linch, D.C. (1990) Development of antibodies to unprotected glycosylation sites on recombinant human GM-CSF.Lancet 335, 434.PubMedCrossRefGoogle Scholar
  29. 29.
    von Wussow, P., Pralle, H., Hochkeppel, H.-K., Jakschies, D., Sonnen, S., Schmidt, H., Müller-Rosenau, P., Franke, M., Haferlach, T., Zwingers, T., Rapp, U. and Deicher, H. (1991) Effective natural interferon-a therapy in recombinant interferon-Q-resistant patients with hairy cell leukaemia.Blood 78, 38.Google Scholar
  30. 30.
    Russo, D., Candoni, A., Zuffa, E., Minisini, R., Silvestri, F., Fanin, R., Zaja, F., Martinelli, G., Tura, S., Botta, G. and Baccarani, M. (1996) Neutralizing anti-interferon-a antibodies and response to treatment in patients with Ph+ chronic myeloid leukaemia sequentially treated with recombinant (a2a) and lymphoblastoid interferon-a.Br. J. Haematol 94, 300.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 1996

Authors and Affiliations

  • Peter Ragnhammar
    • 1
  • Meenu Wadhwa
    • 2
  1. 1.Department of Oncology (Radiumhemmet)Karolinska HospitalStockholmSweden
  2. 2.Division of Immunbio logyNational Institute for Biological Standards and ControlHertfordshireUK

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