Medical Oncology

, Volume 13, Issue 3, pp 167–176 | Cite as

Anti-tumoral effect of GM-CSF with or without cytokines and monoclonal antibodies in solid tumors

  • Peter Ragnhammar


Cytotoxicity is an important function of the immune system that results in destruction of cellular targets by humoral and cellular mechanisms. The functional capacity of granulocytes, lymphocytes and macrophages are of significance for cancer patients because of the ability of these cells to exhibit anti-tumor activity. The hallmark of immune cytotoxicity is the recognition and destruction of selected targets by humoral and cellular effects that distinguish between targets and normal cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine with potential to be an anti-neoplastic cytokine. GM-CSF induces: (1) differentiation of monocytes to large macrophage like cells; (2) augmentation of MHC class II antigen expression on monocytes; (3) enhancementin vitro of macrophage and granulocyte natural cytotoxicity and ADCC; and (4) increased expression of adhesion molecules on granulocytes and monocytes. GM-CSF also cooperates with other cytokines in the expansion of specific T cells. Several experimental and clinical studies have demonstrated the anti-neoplastic effects of GM-CSF alone or in combination with cytokines or/and monoclonal antibody. Interestingly, the future might see the combination of GM-CSF and mouse monoclonal antibody MAbl7-lA in the adjuvant setting in colon- and/or rectal carcinoma patients.


GM-CSF cytokines monoclonal antibodies 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Burgess, A.W., Camakaris, J. and Metcalf, D. (1977) Purification and properties of colony stimulating factor from mouse lung conditioned medium.J. Biol. Chem. 252, 1998–2003.PubMedGoogle Scholar
  2. 2.
    Huebner, K., Isobe, M., Croce, CM. et al. (1985) The human gene encoding GM-CSF is at 5q21-q32, the chromosome region deleted in the 5q-anomaly.Science 230, 1282–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Schrader, J.W., Ziltener, H.J. and Leslie, K.B. (1986) Structural homologies among the hemopoietins.Proc. Natl. Acad. Sci. USA 83, 2458–62.PubMedCrossRefGoogle Scholar
  4. 4.
    Gearing, D.P., King, J.A. and Gough, N.M. (1989) Expression cloning of a receptor for human granulocyte-macro- phage colony-stimulating factor.EMBO J. 8, 3667–76.PubMedGoogle Scholar
  5. 5.
    Hayashida, K., Kitamura, T., Gorman, D.M. et al (1990) Molecular cloning of a second subunit of the receptor for human granulocyte-macrophage colony-stimulating factor (GM-CSF): reconstitution of a high-affinity GM-CSF receptor.Proc. Natl. Acad. Sci. USA 87, 9655–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Clark, S.C. and Kamen, R. (1987) The human hematopoietic colony-stimulating factors.Science 236, 1229–37.PubMedCrossRefGoogle Scholar
  7. 7.
    Dinarello, C.A. and Mier, J.VV. (1987) Lymphokines. TV.Engl. J. Med. 317, 940–5.CrossRefGoogle Scholar
  8. 8.
    Colotta, F., Wang, J.M. and Polentarutti, N. (1987) Expression of c-fos protooncogene in normal human peripheral blood granulocytes.J. Exp. Med. 165, 1224–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Lindemann, A., Riedel, D., Oster, al. (1988) Granulo- cyte/macrophage colony-stimulating factor induced inter- leukin 1 production by human polymorphonuclear neutrophils.J. Immunol. 140, 837–9.PubMedGoogle Scholar
  10. 10.
    Cicco, N.A., Lindemann, A., Content, al. (1990) Inducible production of interleukin-6 by human polymorphonuclear neurrophils: role of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha.Blood 75, 2049–52.PubMedGoogle Scholar
  11. 11.
    Lindemann, A., Riedel, D., Oster, W. et al. (1989) Granulocyte-macrophage colony-stimulating factor induces cytokine secreting by human polymorphonuclear leukocytes.J. Clin. Invest. 83, 1308–12.PubMedCrossRefGoogle Scholar
  12. 12.
    Villalta, F. and Kierszenbaum, F. (1986) Effects of human colony-stimulating factor on the uptake and destruction of a pathogenic parasite (trypanosome cruzi) by human neutrophils.J. Immunol 137, 1703–7.PubMedGoogle Scholar
  13. 13.
    Fabian, L, Baldwin, G.C. and Golde, D.W. (1987) Biosynthetic granulocyte-macrophage colony-stimulating factor enhances neutrophil cytotoxicity toward human leukemia cells.Leukemia 1, 613–7.PubMedGoogle Scholar
  14. 14.
    Weisbart, R.H., Kwan, L., Golde, D.W. et al. (1987) Human GM-CSF primes neutrophils for enhanced oxidative metabolism in responseto the major physiological chemoattractants.Blood 69, 18–21.PubMedGoogle Scholar
  15. 15.
    Masucci, G., Wersäll, P. and Ragnhammar, P. (1989) Gran- ulocyte-monocyte-colony-stimulating factor augments the cytotoxic capacity of lymphocytes and monocytes in antibody dependent cellular cytotoxicity.Cancer Immunol. Immunother. 29, 288–92.PubMedCrossRefGoogle Scholar
  16. 16.
    Liesveld, J.L., Abboud, C.N., Looney, al. (1988) Expression of IgG Fc receptors in myeloid leukemic cell lines. Effect of colony-stimulating factors and cytokines.J. Immunol. 140, 1527–33.PubMedGoogle Scholar
  17. 17.
    Grabstein, K.H., Urdal, D.L., Tushinski, R.J., Mochizuki, D.Y., Price, V.L., Cantrell, M.A., Gillis, S. and Conlon, P. (1986) Induction of macrophage tumoricidal activity by granulocyte-macrophage colony-stimulating factor.Science 232, 506–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Yamashita, Y., Nara, N. and Aoki, N. (1989) Antiproliferative and differentiative effect of granulocyte-macrophage colony-stimulating factor on a variant human small cell lung cancer cell line.Cancer Res. 49, 5334–8.PubMedGoogle Scholar
  19. 19.
    Ruff, M.R., Farrar, W.L. and Pert, C.B. (1986) Interferon γ and granulocyte/macrophage colony-stimulating factor inhibit growth and induce antigen characteristic of myeloid differentiation in small-cell lung cancer cell lines.Proc. Natl. Acad. Sci. USA 83, 6613–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Baldwin, C.C., DiPersio, J., Kaufman, S.E., Quan, S.G., Golde, D.V. and Gasson, J.C. (1987) Characterization of human GM-CSF receptors on non hematopoietic cells.Blood 70, (suppl. 1), 166a.Google Scholar
  21. 21.
    Ragnhammar, P., Frödin, J-E., Trotta, P.P. and Mellstedt, H. (1994) Cytotoxicity of white blood cells activated by granulocyte-colony-stimulating factor, granulocyte/macro- phage-colony-stimulating factor and macrophage-colony-stimulating factor against tumor cells in the presence of various monoclonal antibodies.Cancer Immunol. Immunother. 39, 254–62.PubMedCrossRefGoogle Scholar
  22. 22.
    Silberstein, D.S., Owen, W.F., Gasson, J.C, DiPersio, J.F., Golde, D.W., Bina, J.C, Sobermann, R., Austen, K.F. and David, J.F. (1986) Enhancement of human eosinophil cytotoxicity and leukotriene synthesis by biosynthetic (recombinant) granulocyte-macrophage colony-stimulating factor.J. Immunol. 137, 3290–4.PubMedGoogle Scholar
  23. 23.
    Fidler, I.J. and Schroit, A.J. (1988) Recognition and destruction of neoplastic cells by activated macrophages: discrimination of altered self.Biochim. Biophys. Acta 948, 151–73.PubMedGoogle Scholar
  24. 24.
    Nathan, CF., Murray, H.C. and Cohn, Z.A. (1980) The macrophage as an effector cell.N. Engl. J. Med. 303, 622–6.PubMedGoogle Scholar
  25. 25.
    Hibbs, J.B. Jr (1974) Heterocytolysis by macrophages activated by bacillus Calmette-Guerin: lysosome exocytosis into tumor cells.Science 184, 468–71.PubMedCrossRefGoogle Scholar
  26. 26.
    Yamauchi, N., Kuriyama, H., Watanabe, N., Neda, H., Maeda, M. and Niitsu, Y. (1989) Intracellular hydroxyl radical production induced by recombinant human tumor necrosis factor and its implication in the killing of tumor cells in vitro.Cancer Res. 49, 1671–5.PubMedGoogle Scholar
  27. 27.
    Dillman, R.O. (1987) In R.K. Oldham (ed.)Principles of cancer biotherapy, pp. 291–318. New York: Raven Press, Ltd.Google Scholar
  28. 28.
    Liesveld, J.L., Frediani, K.E., Winslow, J.M., Duerst, R.E. and Abboud, C.N. (1991) Cytokine effects and role of adhesive proteins and Fc receptors in human macro- phage-mediated antibody dependent cellular cytotoxicity.J. Cell. Biochem. 45, 381–90.PubMedCrossRefGoogle Scholar
  29. 29.
    Connor, R.I., Shen, L. and Fanger, M.W. (1990) Evaluation of the antibody-dependent cytotoxic capabilities of individual human monocytes. Role of FCγRI and FCγRII and the effects of cytokines at the single cell level.J. Immunol. 145, 1483–9.PubMedGoogle Scholar
  30. 30.
    Masucci, G., 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, 288–92.PubMedCrossRefGoogle Scholar
  31. 31.
    Kushner, B.H. and Cheung, N-K.V. (1989) GM-CSF enhances 3F8 monoclonal antibody-dependent cellular cytotoxicity against human melanoma and neuroblastoma.Blood 73, 1936–41.PubMedGoogle Scholar
  32. 32.
    Epling-Burnette, P.K., Wei, S., Blanchard, D.K., Spanzi, E. and Djeu, Y. (1993) Coinduction of granulocyte-macro- phage colony-stimulating factor release and lymphokine- activated killer cell susceptibility in monocytes by inter- leukin-2 via interleukin-2 receptor.Blood 81, 3130–7.PubMedGoogle Scholar
  33. 33.
    Baxevanis, C.N., Dedoussis, G.V.Z., Papadopoulos, N.G., Missitzis, I., Beroukas, C, Stathopoulos, G.P. and Papa-ichail, M. (1995) Enhanced human lymphokine-activated killer cell function after brief exposure to granulocyte- macrophage-colony stimulating factor.Cancer 76, 1253–60.PubMedCrossRefGoogle Scholar
  34. 34.
    Wos, E., Olencki, T., Tuason, L., Budd, G.T., Peereboom, D., Sandstrom, K., McLain, D., Finke, J. and Bukowski, R.M. (1996) Phase II trial of subcutaneously administered granulocyte-macrophage colony-stimulating factor in patients with metastatic renal cell carcinoma.Cancer 77, 1149–53.PubMedCrossRefGoogle Scholar
  35. 35.
    Wing, E.J., Magee, D.M., Whiteside, T.L., Kaplan, S.S. and Shadduck, R.K. (1989) Recombinant human granulocyte/macrophage colony-stimulating factor enhances monocyte cytotoxicity secretion of tumor necrosis factor α and interferon in cancer patients.Blood 73, 643–6.PubMedGoogle Scholar
  36. 36.
    Steis, R.G., VanderMolen, L.A., Longo, D.L., Clark, J.W., Smith, J.W., Kopp, W.C., Ruscetti, F.W., Creekmore, S.P.,. Elwood, L.J., Hursey, J. and Urba, W.J. (1990) Recombinant human granulocyte-macrophage colony-stimulating factor in patients with advanced malignancy: A phase Ib trial.J. Natl. Cancer Inst. 82, 697–703.PubMedCrossRefGoogle Scholar
  37. 37.
    Chachoua, A., Oratz, R. Hoogmoed, R., Caron, D., Peace, D., Liebes, L., Blum, R.H. and Vilcek, J. (1994) Monocyte activation following systemic administration of granulocyte-macrophage colony-stimulating factor.J. Immunother. 15, 217–24.CrossRefGoogle Scholar
  38. 38.
    Bukowski, R.M., Murthy, S., McLain, D., Finke, J., Andresen, S., Tubbs, R., Bauer, L., Gibson, V., Budd, G.T. and Thomassen, M.J. (1993) Phase I trial of recombinant granulocyte-macrophage colony-stimulating factor in patients with lung cancer: Clinical and immunologic effects.J. Immunother. 13, 267–74.CrossRefGoogle Scholar
  39. 39.
    Lieschke, G.J., Maher, D., O’Connor, M., Green, M., Sheridan, W., Railings, M., Bonnern, E., Burgess, A.W., McGrath, K., Fox, R.M. and Morstyn, G. (1990) Phase I study of intravenously administered bacterially synthesized granulocyte-macrophage colony-stimulating factor and comparison with subcutaneous administration.Cancer Res. 50, 606–14.PubMedGoogle Scholar
  40. 40.
    Herrmann, F., Schultz, G., Lindemann, A., Meyenburg, W., Oster, W., Krumwieh, D. and Mertelsmann, R. (1989) Hematopoietic responses in patients with advanced malignancy treated with recombinant human granulocyte- macrophage colony-stimulating factor.J. Clin. Oncol. 7, 159–67.PubMedGoogle Scholar
  41. 41.
    O’Donnell, R.T., Dea, G. and Meyers, F.J. (1995) A phase II trial of concomitant interferon-α-2b and granulocyte- macrophage colony-stimulating factor in patients with advanced renal cell carcinoma.J. Immunother. 17, 58–61.CrossRefGoogle Scholar
  42. 42.
    Schiller, J.H., Hank, J.A., Khorsand, M, Storer, B., Borchert, A., Huseby-Moore, K., Burns, D., Wesly, O., Albertini, M.R., Wilding, G. and Sondel, P.M. (1996) Clinical and immunological effect of granulocyte-macrophage colony- stimulating factor coadministered with interleukin 2: A phase IB study.Clin. Cancer Res. 2, 319–30.PubMedGoogle Scholar
  43. 43.
    Ragnhammar, P., Fagerberg, J., Frödin. J-E., Hjelm, A-L., Lindemalm, C, Magnusson, I., Masucci, G. and Mell-stedt, H. (1993) Effect of monoclonal antibody 17-1A and GM-CSF in patients with advanced colorectal carcinoma — long lasting, complete remissions can be induced.Int. J. Cancer 53, 751–8.PubMedCrossRefGoogle Scholar
  44. 44.
    Ragnhammar, P., Masucci, G., Frödin, J-E., Hjelm, A-L. and Mellstedt, H. (1992) Cytotoxic functions of blood mononuclear cells in patients with colorectal carcinoma treated with mAb 17-1A and granulocyte/macrophage-colony-stimulating factor.Cancer Immunol. Immunother. 35, 158–64.PubMedCrossRefGoogle Scholar
  45. 45.
    Chachoua, A., Oratz, R., Liebes, L., Alter, R.S., Felice, A., Peace, D., Vilcek, J. and Blum, R.H. (1994) Phase Ib trial of granulocyte-macrophage colony-stimulating factor combined with murine monoclonal antibody R24 in patients with metastatic melanoma.J. Immunother. Emphasis Tumor Immunol. 16, 132–41.PubMedGoogle Scholar
  46. 46.
    Schmid, I., Baldwin, G.C., Jacobs, E.L., Isacescu, V., Neagos, N., Giorgi, J.V. and Glaspy, J.A. (1995) Alterations in phenotype and cell-surface antigen expression levels of human monocytes: Differential response toin vivo administration of rhM-CSF or rhGM-CSF.Cytometry 22, 103–10.PubMedCrossRefGoogle Scholar
  47. 47.
    Masucci, G., Ragnhammar, P., Wersäll, P. and Mellstedt, H. (1990) Granulocyte-monocyte colony-stimulating factor augments the interleukin-2-induced cytotoxic activity of human lymphocytes in the absence and presence of mouse or chimeric monoclonal antibodies (mAb 17-1 A).Cancer Immunol. Immunother. 31, 231–5.PubMedCrossRefGoogle Scholar
  48. 48.
    Hjelm-Skog, A-L., Frödin, J-E., Ragnhammar, P., Goldinger, M., Koldestam, H., Liljefors, M., Wersäll, P. and Mellstedt, H. (1996) Effect of monoclonal antibody 17-1A, GM-CSF and IL-2 in patients with advanced colorectal carcinoma, (in manuscript).Google Scholar
  49. 49.
    Young, D.A., Lowe, L.D. and Clark, S.C. (1990) Comparison of the effects of IL-3, granulocyte-macrophage colony- stimulating factor and macrophage colony-stimulating factor in supporting monocyte differentiation in culture.J. Immunol. 145, 607–15.PubMedGoogle Scholar
  50. 50.
    Robin, G., Markovich, S., Athamna, A. and Keisary, Y. (1991) Human recombinant granulocyte-macrophage colony-stimulating factor augments viability and cytotoxic activities of human monocyte-derived macrophages in long-term cultures.Lymphokine Cytokine Res. 10, 257–63.PubMedGoogle Scholar
  51. 51.
    Steis, R.G., VanderMolen, L.A., Longo, D.L., Clark, J.W., Smith, J.W., Kopp, W.C., Ruscetti, F.W., Creekmore, S.P., Elwood, L.J., Hursey, E.J. and Urba, W.J. (1990) Recombinant human granulocyte-macrophage colony-stimulating factor in patients with advanced malignancy: A phase Ib trial.J. Natl. Cancer Inst. 82, 697–703.PubMedCrossRefGoogle Scholar
  52. 52.
    Blanchard, D.K. and Dieu, J.Y. (1991) Differential modulation of surface antigens on human macrophages by IFN- gamma and GM-CSF. — Effect on susceptibility to LAK lysis.J. Leukoc. Biol. 50, 28–34.PubMedGoogle Scholar
  53. 53.
    Grabstein, K.H., Urdal, D.L., Tushinski, R.J., Mochizuki, D.Y., Price, V.J., Cantrell, M.A., Gillis, S. and Conlon, P.J. (1986) Induction of macrophage tumoricidal activity by granulocyte-macrophage colony stimulating factor.Science 232, 506–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Arnaout, M.A., Wang, E.A., Clark, S.C. and Sieff, C.A. (1986) Human recombinant granulocyte-macrophage colony-stimulating factor increases cell-to-cell adhesion and surface expression of adhesion-promoting surface glycoproteins on mature granulocytes.J. Clin. Invest. 78, 597–601.PubMedCrossRefGoogle Scholar
  55. 55.
    Fischer, H.G., Frosch, S., Reske, K. and Reske-Kunz, A.B. (1988) GM-CSF activates macrophages derived from bone marrow cultures to synthesis of MHC class II molecules and to augmented antigen presentation function.J. Immunol. 141, 3882–8.PubMedGoogle Scholar
  56. 56.
    Santoli, D., Clark, S.C, Kreider, B.L., Patricia, A.M., Maslin, A. and Rovera, G. 1998 Amplification of IL-2 driven T-cell proliferation by recombinant human IL-3 and granulocyte-macrophage colony stimulating factor.J.Immunol. 141, 519–26.Google Scholar
  57. 57.
    Dranoff, G., Jaffee, E., Lazenby, A., Golumbeck, P., Levitsky, H., Brose, K., Jackson, V., Hamada, H., Pardoll, D. and Mulligan, R. (1993) Vaccination with irradiated tumor cells engineered to secret murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity.Proc. Natl. Acad. Sci. USA 90, 3539–43.PubMedCrossRefGoogle Scholar
  58. 58.
    Steward, W.P., Scarffe, J.H., Austin, R., Bonnern, E., Thatcher, N., Morgenstern, G. and Crowther, D. (1989) Recombinant human granulocyte macrophage colony stimulating f actor (rhGM-CSF) given as daily short infusions — a phase I dose-toxicity study.Br. J. Cancer 59, 142–5.PubMedGoogle Scholar
  59. 59.
    Boente, P., Sampaio, C, Brandao, M., Moreira, E., Badaro, R. and Jones, T. (1993) Local peri-lesional therapy with rhGM-CSF for Kaposi’s sarcoma.Lancet 341, 1154.PubMedCrossRefGoogle Scholar
  60. 60.
    Herlyn, D., Herlyn, M., Ross, A.H., Ernst, C, Atkins, B. and Koprowski, H. (1984) Efficient selection of human tumor growth-inhibiting monoclonal antibodies.J. Immunol Methods. 73, 157–67.PubMedCrossRefGoogle Scholar
  61. 61.
    Mellstedt, H., Frodin, J-E., Masucci, G., Ragnhammar, P., Fagerberg, J., Hjelm, A-L., Shetye, J., Wersäll, P. and Österborg, A. (1991) The therapeutic use of monoclonal antibodies in colorectal carcinoma.Semin. Oncol. 18, 462–77.PubMedGoogle Scholar
  62. 62.
    Tao, M-H. and Levy, R. (1993) Idiotype/granulocyte-macro-phage colony-stimulating factor fusion protein as a vaccine for B-cell lymphoma.Nature 362, 755–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Morrissey, P.J., Bressler, L., Park, L.S., Alpert, A. and Gilllis, S. (1987) Granulocyte-macrophage colony-stimulating factor augments the primary antibody response by enhancing the function of antigen-presenting cells.J. Immunol. 139, 1113–9.PubMedGoogle Scholar
  64. 64.
    Hill, A.D.K., Redmond, H.P., Naama, H.A. and Bouchier-Hayes, D. (1995) Granulocyte-macrophage colony-stimulating factor inhibits tumor growth during the postoperative period.Surgery 119, 178–85.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 1996

Authors and Affiliations

  • Peter Ragnhammar
    • 1
  1. 1.Department of Oncology (Radiumhemmet)Karolinska HospitalStockholmSweden

Personalised recommendations