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Monocyte/Macrophage Activation by Immunostimulators

Role in Cancer Therapy

  • Review Article
  • Immunological Basis of Disease
  • Published:
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Summary

Cells of the monocyte/macrophage lineage are considered to be of special importance in host defence against tumour growth. There is experimental and clinical evidence that in malignant disease the generation of cytotoxic macrophages is impaired. Both defective cell maturation and loss of responsiveness to activation have been described. Immunotherapeutic strategies to stimulate macrophage tumour cytotoxicity make use of activating compounds such as interferon-γ (IFNγ), endotoxin (lipopolysaccharide) and other cytokines that are administered systemically.

Subcutaneous treatment with low-dose IFNγ given on a weekly schedule achieved an objective response of 4 to 30% in patients with metastatic renal cell carcinoma. Higher doses of IFNγ were given intravenously and achieved an objective response in 9% and stable disease in 49% of patients with renal cell carcinoma. Lipopolysaccharide given intravenously induced a profound immunological response in the recipient. Antitumour activity was seen in 25% of patients with advanced cancer.

Adoptive immunotherapy with macrophages generated in vitro is a treatment modality designed to correct for defective in vivo maturation of monocytes. Preclinical data in murine models showed a remarkable antitumour effect of transferred cells. Activated macrophages given locally or via intravenous injection inhibited tumour growth of Lewis lung carcinoma by 30 to 40% in C57B16 mice. Clinical trials with local and systemic transfer of autologous cytotoxic macrophages showed the induction of neopterin, interleukin-6 and thrombin-antithrombin complexes in the recipient. The antitumour activity of local therapy was evident from the disappearance of malignant ascites upon intraperitoneal cell application. However, as reported by several groups, intravenous cell transfer has yielded conflicting results and only minor tumour responses were seen. Here, further improvements in culture technique and mode of cell activation are being developed.

In addition, macrophages could be used as a target of gene transfer experiments. The therapeutic value of this technique needs careful investigation.

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References

  1. van Furth R. Cell biology of mononuclear phagocytes. In: van Furth R, editor. Hematopoietic growth factors and mononuclear phagocytes. Basel: Karger, 1993

    Google Scholar 

  2. Andreesen R, Osterholz J, Bross KJ, et al. Cytotoxic effector cell function at different stages of human monocyte-macrophage maturation. Cancer Res 1983; 43: 5931–6

    PubMed  CAS  Google Scholar 

  3. Scheibenbogen C, Zenke G, Faggs B, et al. Secretion of colonystimulation factor for macrophages (M-CSF) and granulocytes/macrophages (GM-CSF) is developmentally regulated. In: Freund M, Linke H, Weite K, editors. Human macrophages and cytokines in hematopoiesis, oncology and AIDS. Berlin, Heidelberg: Springer Verlag, 1990

    Google Scholar 

  4. Lavnikova N, Drapier JC, Laskin DL. A single exogenous stimulus activates resident rat macrophages for nitric oxide production and tumor cytotoxicity. J Leukoc Biol 1993; 54: 322–8

    PubMed  CAS  Google Scholar 

  5. Andreesen R, Scheibenbogen C, Kreutz M, et al. Regulation of neopterin secretion during human monocyte to macrophage differentiation in vitro. Pteridines 1990; 2: 59–61

    Article  CAS  Google Scholar 

  6. Scheibenbogen C, Andreesen R. Developmental regulation of the cytokine repertoire in human macrophages: IL-1, IL-6, TNF-α and M-CSF. J Leukoc Biol 1991; 50: 35–42

    PubMed  CAS  Google Scholar 

  7. Schwamberger G, Flesch I, Ferber E. Characterisation and purification of a high molecular weight tumoricidal activity secreted by murine bone marrow macrophages. Int Immunol 1992; 4: 253–64

    Article  PubMed  CAS  Google Scholar 

  8. Somers SD, Johnson WJ, Adams DO. Destruction of tumor cells by macrophages: mechanisms of recognition and lysis and their regulation. In: Herberman RB, editor. Cancer immunology: innovative approaches to therapy. Boston, London: Martinus Nijhoff Publishers, 1986

    Google Scholar 

  9. Petit JF, Phan-Bich L, Lemaire G, et al. During their differentiation into macrophages human monocytes acquire cytostatic activity independent of nitric oxide and TNF-α. Res Immunol 1993; 144: 265–98

    Article  Google Scholar 

  10. Charak BS, Agah R, Mazumder A. Granulocyte-macrophage colony-stimulating factor-induced antibody-dependent cellular cytotoxicity in bone marrow macrophages: application in bone marrow transplantation. Blood 1993; 81(12): 3474–9

    PubMed  CAS  Google Scholar 

  11. Munn DH, Cheung NK. Antibody-dependent antitumor cytotoxicity by human monocytes cultured with recombinant macrophage colony-stimulating factor. J Exp Med 1989; 170: 511–26

    Article  PubMed  CAS  Google Scholar 

  12. Currie GA. Activated macrophages kill tumor cells by releasing arginase. Nature 1978; 273: 758–9

    Article  PubMed  CAS  Google Scholar 

  13. Bentley C, Bitter-Suermann D, Hadding U, et al. In vitro synthesis of factor B of the alternative pathway of complement activation by mouse peritoneal macrophages. Eur J Immunol 1976; 6: 393–8

    Article  PubMed  CAS  Google Scholar 

  14. Goodman MG, Weigle WO, Hugli TE. Inability of the C3a anaphylaxatoxin to promote cellular lysis. Nature 1980; 283: 78–80

    Article  PubMed  CAS  Google Scholar 

  15. Gordon S. Lysozyme and plasminogen activator — constitutive and induced secretory products of mononuclear phagocytes. In: van Furth R, editor. Mononuclear phagocytes. The Hague: Nijhoff Publishers, 1980: 1273

    Google Scholar 

  16. Johnson WI, Weiel JE, Adams DO. The relationship between secretion of a novel cytolytic protease and macrophage-mediated tumor cytotoxicity. In: Herbermann R, editor. Natural cell-mediated immunity II. New York: Academic Press, 1982: 949–54

    Google Scholar 

  17. Fomsgaard A, Worsaae H, Bendtzen K. Detection of tumor necrosis factor from lipopolysaccharide-stimulated human mononuclear cells by enzyme-linked immunoabsorbent assay and cytotoxicity bioassay. Scand J Immunol 1988; 27: 143–7

    Article  PubMed  CAS  Google Scholar 

  18. Metzger Z, Hoffeld JT, Oppenheim JJ. Macrophage-mediated suppression: I. Evidence for participation of both hydrogen peroxide and prostaglandins in suppression of murine lymphocyte proliferation. J Immunol 1980; 124: 983–8

    PubMed  CAS  Google Scholar 

  19. Adams DO, Johnson WJ, Fiorita E, et al. H2O2 and CF can interact synergistically in effecting cytolysis of neoplastic targets. J Immunol 1973; 127: 120–2

    Google Scholar 

  20. Rosztoczy I, Content J. The effect of various cytokines on interleukin-6 and interferon-α synthesis in human peripheral blood mononuclear cells. J Interferon Res 1990; 10: 637–45

    Article  PubMed  CAS  Google Scholar 

  21. Meyernik D, Haq A, Rinehard JJ. Interleukin-1 secretion by human monocytes and macrophages. J Leukoc Biol 1984; 36: 551–7

    Google Scholar 

  22. Davies P, Page RC, Allison AC. Changes in cellular enzyme levels and extracellular release of lysosomal acid hydrolases in macrophages exposed to group A streptococcal wall substance. J Exp Med 1974; 139: 1262–82

    Article  PubMed  CAS  Google Scholar 

  23. Gordon S, Todd J, Cohn ZA. In vitro synthesis and secretion of lysozyme by mononuclear phagocytes. J Exp Med 1974; 139: 1228–48

    Article  PubMed  CAS  Google Scholar 

  24. Drysdale BE, Zachachutz CM, Shin HS. Mechanism of macrophage-mediated cytotoxicity: production of a soluble cytotoxic factor. J Immunol 1983; 131: 2362–7

    PubMed  CAS  Google Scholar 

  25. Stadecker MJ, Unanue ER. The regulation of thymidine secretion by macrophages. J Immunol 1979; 123: 568–71

    PubMed  CAS  Google Scholar 

  26. Kreutz M, Andreesen R, Krause S, et al. 1,25-Dihydroxyvitamin D3 production and vitamin D3 receptor expression are developmentally regulated during differentiation of human monocytes into macrophages. Blood 1993; 82: 1300–7

    PubMed  CAS  Google Scholar 

  27. Adams DO, Hamilton TA. The cell biology of macrophage activation. Annu Rev Immunol 1984; 2: 283–318

    Article  PubMed  CAS  Google Scholar 

  28. Schwamberger G, Flesch I, Ferber E. Tumoricidal effector molecules of murine macrophages. Pathobiology 1991; 59: 248–53

    Article  PubMed  CAS  Google Scholar 

  29. Fidler IJ, Kleinermann ES. Lymphokine-activated human blood monocytes destroy tumor cells but not normal cells under cocultivation conditions. J Clin Oncol 1984; 2: 937–43

    PubMed  CAS  Google Scholar 

  30. Shimizu H, Wyatt K, Knowles RD, et al. Human monocytes selectively bind to cells expressing the tumorigenic phenotype. Cancer Immunol Immunother 1989; 28: 185–92

    Article  PubMed  CAS  Google Scholar 

  31. Fidler IJ. Recognition and destruction of target cells by tumoricidal macrophages. Isr J Med Sci 1978; 14: 177–92

    PubMed  CAS  Google Scholar 

  32. Lee AM, Vadhan-Raj S, Hamilton RF, et al. The in vivo effects of rhIL-lα therapy on human monocyte activity. J Leukoc Biol 1993; 54: 314–21

    PubMed  CAS  Google Scholar 

  33. Andreesen R, Osterholz J, Luckenbach GA, et al. Tumor cytotoxicity of human macrophages after incubation with synthetic analogues of 2-lysophosphatidylcholine. J Natl Cancer Inst 1984; 72: 53–9

    PubMed  CAS  Google Scholar 

  34. Saiki I, Fidler IJ. Synergistic activation by recombinant mouse interferon-gamma and muramyl dipeptide of tumoricidal properties in mouse macrophages. J Immunol 1985; 135: 684–8

    PubMed  CAS  Google Scholar 

  35. Nathan C, Cohn ZA. Role of oxygen-dependent mechanisms in antibody-induced lysis of tumor cells by activated macrophages. J Exp Med 1980; 152: 198–208

    Article  PubMed  CAS  Google Scholar 

  36. Koren HS, Andreson SJ, Adams DO. Studies on the antibodydependent cell-mediated cytotoxicity (ADCC) of thiaglycollate-stimulated and BCG-activated peritoneal macrophages. Cell Immunol 1981; 57: 51–61

    Article  PubMed  CAS  Google Scholar 

  37. Koren HS, Meltzer MS, Adams DO. The ADCC capacity of macrophages from C3H/HEJ and A/J mice can be augmented by BCG. J Immunol 1981; 126: 1013–15

    PubMed  CAS  Google Scholar 

  38. Steplewski Z, Herlyn D, Maul G, et al. Hypothesis: macrophages as effector cells of human tumor destruction mediated by monoclonal antibodies. Hybridoma 1983; 2: 1–5

    Article  PubMed  CAS  Google Scholar 

  39. Langlois AJ, Matthews TJ, Roloson GJ, et al. Immunologic control of the ascites form of murine adenocarcinoma 755: V. antibody-directed macrophages mediate tumor cell destruction. J Immunol 1981; 126: 2337–41

    PubMed  CAS  Google Scholar 

  40. Johnson WJ, Steplewski Z, Matthews TJ, et al. Cytolytic interactions between murine macrophages, tumor cells and monoclonal antibodies: characterization of lytic conditions and requirements for effector activation. J Immunol 1986; 136: 4704–13

    PubMed  CAS  Google Scholar 

  41. Nathan CF, Silverstein SC, Bruckner LH, et al. Extracellular cytolysis by activated macrophages and granulocytes: II. Hydrogen peroxide as a mediator of cytotoxicity. J Exp Med 1979; 149: 100–13

    Article  PubMed  CAS  Google Scholar 

  42. Johnson WJ, Bolognesi DP, Adams DO. Antibody dependent cytolysis (ADCC) of tumor cells by activated murine macrophages is a two step process: quantification of target binding and subsequent target lysis. Cell Immunol 1984; 83: 170–80

    Article  PubMed  CAS  Google Scholar 

  43. Munn DH, Cheung NK. Phagocytosis of tumor cells by human monocytes cultured in recombinant macrophage colony-stimulating factor. J Exp Med 1990; 172: 231–7

    Article  PubMed  CAS  Google Scholar 

  44. Van de Loosdrecht AA, Ossenkoppele GJ, Beelen RHJ, et al. Maturation-dependent susceptibility to monocyte-mediated cytotoxicity in acute myeloid leukemia. Leukemia 1994; 8: 1392–400

    PubMed  Google Scholar 

  45. Van der Bosch J, Müller S, Horn D, et al. Density-dependent tumor cell death and reversible cell cycle arrest: mutually exclusive modes of monocyte-mediated growth control. Exp Cell Res 1990; 187: 185–92

    Article  PubMed  Google Scholar 

  46. Withworth PW, Pak CP, Esgro J, et al. Macrophages and cancer. Cancer Metastasis Rev 1990; 8: 319–51

    Article  Google Scholar 

  47. Berg JW. Inflammation and prognosis in breast cancer. Cancer 1959; 12: 714–5

    Article  PubMed  CAS  Google Scholar 

  48. Dizon Q, Southam CM. Abnormal cellular response to skin abrasions in cancer patients. Cancer 1963; 16: 1288–92

    Article  PubMed  CAS  Google Scholar 

  49. Eccles SA, Alexander P. Macrophage content of tumors in relation to metastatic spread and host immune reaction. Nature 1974; 250: 667–9

    Article  PubMed  CAS  Google Scholar 

  50. Russell SW, McIntosh AT. Macrophages isolated from regressing Moloney sarcomas are more cytotoxic than recovered from progressing sarcomas. Nature 1977; 268: 69–71

    Article  PubMed  CAS  Google Scholar 

  51. Fauve RM, Hevin B, Jacob H, et al. Antiinflammatory effects of murine malignant cells. Proc Natl Acad Sci USA 1974; 71: 4072–4

    Article  Google Scholar 

  52. Cianciolo GJ. Antiinflammatory effects of neoplasms. Res Immunol 1993; 144: 268–71

    Article  PubMed  CAS  Google Scholar 

  53. Lindvall M, Sjögren HO. Inhibition of rat yolk sac tumor growth in vivo by a monoclonal antibody to the retroviral molecule P15E. Cancer Immunol Immunother 1991; 33: 21–7

    Article  PubMed  CAS  Google Scholar 

  54. Schultz RM, Stoychkov JN, Pavlidis N, et al. Role of E-type prostaglandins in the regulation of interferon-treated macrophage cytotoxic activity. J Reticuloendothel Soc 1979; 26: 93–102

    PubMed  CAS  Google Scholar 

  55. Leung KH, Fischer DG, Koren HS. Erythromyeloid tumor cells (K562) induce PGE synthesis in human peripheral blood monocytes. J Immunol 1983; 131: 445–9

    PubMed  CAS  Google Scholar 

  56. Van Damme J, Proost P, Lenaerts JP, et al. Structural and functional identification of two human, tumor-derived monocyte chemotactic proteins (MCP-2 and MCP-3) belonging to the chemokine family. J Exp Med 1992; 176: 59–69

    Article  PubMed  Google Scholar 

  57. Mantovani A, Bottazzi B, Colotta F, et al. The origin and function of tumor-associated macrophages. Immunol Today 1992; 13: 265–70

    Article  PubMed  CAS  Google Scholar 

  58. Assoian RK, Fleurdelys BE, Stevenson HC, et al. Expression and secretion of type B transforming growth factor by activated human macrophages. Proc Natl Acad Sci USA 1987; 84: 6020–4

    Article  PubMed  CAS  Google Scholar 

  59. Polverini PJ, Leibovich SJ. Induction of neovascularization in vivo and endothelial proliferation in vitro by tumor-associated macrophages. Lab Invest 1984; 51: 635–42

    PubMed  CAS  Google Scholar 

  60. Andreesen R, Kreutz M. Differentiation of human monocytes in vitro: a model of macrophage ontogeny. In: Fusenig NE, Graf H, editors. Cell culture in pharmaceutical research. Berlin: Springer Verlag, 1994: 9–27

    Chapter  Google Scholar 

  61. Andreesen R, Bross KJ, Osterholz J, et al. Human macrophage maturation and heterogeneity: analysis with a newly generated set of monoclonal antibodies to differentiation antigens. Blood 1986; 67: 1257–64

    PubMed  CAS  Google Scholar 

  62. Andreesen R, Brugger W, Gadd S, et al. Activation of human monocyte-derived macrophages cultured on teflon: response to interferon-gamma during terminal maturation in vitro. Immunobiology 1988; 177: 186–98

    Article  PubMed  CAS  Google Scholar 

  63. Fidler IJ. Targeting of immunomodulators to mononuclear phagocytes for therapy of cancer. Adv Drug Delivery Rev 1988; 1: 69–106

    Article  Google Scholar 

  64. Tanguay S, Bucana CD, Wilson MR, et al. In vivo modulation of macrophage tumoricidal activity by oral administration of the liposome-encapsulated macrophage activator CGP 19835A. Cancer Res 1994; 54: 5882–8

    PubMed  CAS  Google Scholar 

  65. Kleinermann ES, Murray JL, Snyder JS, et al. Activation of tumoricidal properties in monocytes from cancer patients following intravenous administration of liposomes containing muramyl tripeptide phosphatidylethanolamine. Cancer Res 1989; 49: 4665–70

    Google Scholar 

  66. Kleinermann ES, Raymond AK, Bucana CD, et al. Unique histological changes in lung metastases of osteosarcoma patients following therapy with liposomal muramyl tripeptide (CGP 19835A lipid). Cancer Immunol Immunother 1992; 34: 211–20

    Article  Google Scholar 

  67. Brown TD, Koeller J, Beaugher K, et al. A phase I clinical trial of recombinant DNA gamma-interferon. J Clin Oncol 1987; 5: 790–8

    PubMed  CAS  Google Scholar 

  68. Aulitzki W, Gastl G, Aulitzki WE, et al. Successful treatment of metastatic renal cell carcinoma with a biologically active dose of recombinant interferon-gamma. J Clin Oncol 1989; 7: 1875–84

    Google Scholar 

  69. Hofmockel G, Wirth MP, Heimbach D, et al. Results of low dosage cyclic interferon-gamma therapy of metastatic renal cell carcinoma. Urologie 1993; 32: 290–4

    CAS  Google Scholar 

  70. Ellerhorst JA, Kilbourn RG, Amato RJ, et al. Phase II trial of low dose gamma-interferon in metastatic renal cell carcinoma. J Urol 1994; 152: 841–5

    PubMed  CAS  Google Scholar 

  71. Garnick MB, Reich SD, Maxwell B, et al. Phase I/II study of recombinant interferon gamma in advanced renal cell carcinoma. J Urol 1988; 139: 251–5

    PubMed  CAS  Google Scholar 

  72. Colombo N, Peccatori E, Paganin C, et al. Anti-tumor and immunomodulatory activity of intraperitoneal IFN-gamma in ovarian carcinoma patients with minimal residual tumor after chemotherapy. Int J Cancer 1992; 51: 42–6

    Article  PubMed  CAS  Google Scholar 

  73. Chen JT, Hasumi K, Masubuchi K. Maintenance of the activation of peritoneal macrophages in patients with ovarian cancer by sizofiran and recombinant interferon-gamma. Biotherapy 1992; 5: 137–43

    Article  PubMed  CAS  Google Scholar 

  74. Greiner JW, Guadagni F, Goldstein D, et al. Intraperitoneal administration of interferon-gamma to carcinoma patients enhances expression of tumor associated glycoprotein-72 and carcinoembryonic antigen on malignant ascites cells. J Clin Oncol 1992; 10: 735–46

    PubMed  CAS  Google Scholar 

  75. Pujade-Lauraine E, Guastella JP, Colombo N, et al. Interféron-gamma par voie intrapéritonéale: un complément efficace de la chimiothérapie des cancers de l’ovaire. À propos d’une étude européenne de 108 patientes. Bull Cancer 1993; 80: 163–70

    PubMed  CAS  Google Scholar 

  76. Jaffe HA, Buhl R, Mastangeli A, et al. Local activation of mononuclear phagocytes by delivery of an aerosol of recombinant interferon-gamma to the human lung. J Clin Invest 1991; 88: 297–302

    Article  PubMed  CAS  Google Scholar 

  77. Boutin C, Nussbaum E, Monnet I, et al. Intrapleural treatment with recombinant gamma-interferon in early stage malignant pleural mesothelioma. Cancer 1994; 74: 2460–7

    Article  PubMed  CAS  Google Scholar 

  78. Jett JR, Maksymiuk AW, Su JQ, et al. Phase III trial of recombinant interferon gamma in complete responders with small-cell lung cancer. J Clin Oncol 1994; 12: 2321–6

    PubMed  CAS  Google Scholar 

  79. Silagi S, Dutkowski R, Schaeffer A. Eradication of mouse melanoma by combined treatment with recombinant human interleukin 2 and recombinant murine interferon gamma. Int J Cancer 1988; 41: 315–22

    Article  PubMed  CAS  Google Scholar 

  80. Redman BG, Flaherty L, Chou TH, et al. A phase I trial of recombinant interleukin-2 combined with recombinant interferon-gamma in patients with cancer. J Clin Oncol 1990; 8: 1269–76

    PubMed  CAS  Google Scholar 

  81. Viens P, Blaise D, Stoppa AM, et al. Interleukin-2 in association with increasing doses of interferon-gamma in patients with advanced cancer. J Immunother 1992; 11: 218–24

    Article  PubMed  CAS  Google Scholar 

  82. Escudier B, Farace F, Angevin E, et al. Combination of interleukin-2 and gamma interferon in metastatic renal cell carcinoma. Eur J Cancer 1993; 29: 724–8

    Article  Google Scholar 

  83. Czarniecki CW, Fennie CW, Powers DB, et al. Synergistic antiviral and antiproliferative activities of E. coli derived human alpha, beta, and gamma interferon. J Virol 1984; 49: 490–6

    PubMed  CAS  Google Scholar 

  84. Hubbell HR, Craft JA, Leibowitz PH, et al. Synergistic antiproliferative effect of recombinant alpha-interferons with recombinant gamma-interferons. J Biol Response Mod 1987; 6: 141–53

    PubMed  CAS  Google Scholar 

  85. Nishisaka N, Yoshihara H, Nakatani T, et al. Clinical study of immunotherapy with interferon alpha and gamma in metastatic renal cell carcinoma. Nippon Hinyokika Gakkai Zasshi 1993; 84: 1987–93

    PubMed  CAS  Google Scholar 

  86. De Mulder PH, Debruyne FM, Franssen MP, et al. Phase I/II study of recombinant interferon alpha and gamma in advanced progressive renal-cell carcinoma. Cancer Immunol Immunother 1990; 31: 321–4

    Article  PubMed  Google Scholar 

  87. De Mulder PH, Oosterhof G, Bouffioux C, et al. EORTC (30885) randomised phase III study with recombinant interferon alpha and recombinant interferon alpha and gamma in patients with advanced renal cell carcinoma: the EORTC Genitourinary Group. Br J Cancer 1995; 71: 371–5

    Article  PubMed  Google Scholar 

  88. Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas: with a report of ten original cases. Am J Med Sci 1893; 105: 487–511

    Article  Google Scholar 

  89. Mitchie HR, Manogue KR, Springs DR, et al. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med 1988; 318; 1481–6

    Article  Google Scholar 

  90. Fong Y, Moldawer LL, Marano M, et al. Endotoxemia elicits increased circulating beta2-IFN/IL-6 in man. J Immunol 1989; 142: 2321–4

    PubMed  CAS  Google Scholar 

  91. Martich GD, Danner RL, Ceska M, et al. Detection of interleukin-8 and tumor necrosis factor in normal humans after intravenous endotoxin: the effect of antiinflammatory agents. J Exp Med 1991; 173: 1021–4

    Article  PubMed  CAS  Google Scholar 

  92. Sack TH, Seligman A. Chemical alteration of polysaccharide from Serratia marcescens: II. Effects of lipopolysaccharide in patients with malignant tumors. J Natl Cancer Inst 1948; 9: 19–34

    PubMed  CAS  Google Scholar 

  93. Vosika GJ, Barr C, Gilsbertson D. Phase I study of intravenous modified lipid A. Cancer Immunol Immunother 1984; 18: 107–12

    Article  PubMed  CAS  Google Scholar 

  94. Engelhardt R, Mackensen A, Galanos C, et al. Biological response to intravenously administered endotoxin in patients with advanced cancer. J Biol Response Mod 1990; 9: 480–91

    PubMed  CAS  Google Scholar 

  95. Engelhardt R, Mackensen A, Galanos C. Phase I trial of intravenously administered endotoxin (Salmonella abortus equi) in cancer patients. Cancer Res 1991; 51: 2524–30

    PubMed  CAS  Google Scholar 

  96. Hume DA, Pavli P, Donahue RE, et al. The effect of human recombinant macrophage colony-stimulating factor (CSF-1) on the murine mononuclear phagocyte system in vivo. J Immunol 1988; 141: 3405–9

    PubMed  CAS  Google Scholar 

  97. Garnick MB, Stoudemire JB. Preclinical and clinical evaluation of recombinant human macrophage colony-stimulating factor (rhM-CSF). Int J Cell Cloning 1990; 8Suppl. 1: 356–73

    Article  PubMed  Google Scholar 

  98. Bajorin DF, Cheung NKV, Houghton AN. Macrophage colonystimulating factor: biological effects and potential applications for cancer therapy. Semin Hematol 1991; 28 Suppl.: 42–8

    PubMed  CAS  Google Scholar 

  99. Sanda MG, Yang JC, Topalian SL, et al. Intravenous administration of recombinant human macrophage colony-stimulating factor (M-CSF) to patients with metastatic cancer: a phase I study. J Clin Oncol 1992; 10: 1643–9

    PubMed  CAS  Google Scholar 

  100. Weiner LM, Li W, Holmes M, et al. Phase I trial of recombinant macrophage colony-stimulating factor and recombinant gamma-interferon: toxicity, monocytosis and clinical effects. Cancer Res 1994; 54: 4084–90

    PubMed  CAS  Google Scholar 

  101. Bukowski RM, Budd GT, Gibbons JA, et al. Phase I trial of subcutaneous recombinant macrophage colony-stimulating factor: clinical and immunomodulatory effects. J Clin Oncol 1994; 12: 97–106

    PubMed  CAS  Google Scholar 

  102. Zamkoff KW, Hudson JG, Groves ES, et al. A phase I trial of recombinant human macrophage colony-stimulating factor by rapid intravenous infusion in patients with refractory malignancy. J Immunother 1992; 11: 103–10

    Article  PubMed  CAS  Google Scholar 

  103. Redman BG, Flaherty L, Chou TH, et al. Phase I trial of recombinant macrophage colony-stimulating factor by rapid intravenous infusion in patients with cancer. J Immunother 1992; 12: 50–4

    Article  PubMed  CAS  Google Scholar 

  104. Hennemann B, Meerpohl HG, Oskam R, et al. A phase I trial of intraperitoneally-administered recombinant macrophage colony stimulating factor (rM-CSF) in cancer patients. Onkologie 1991; 14Suppl. 2: 65

    Google Scholar 

  105. Lopez AF, Williamson DJ, Gamble JR, et al. Recombinant human granulocyte-macrophage colony-stimulating factor stimulates in vitro mature human neutrophil and eosinophil function, surface receptor expression, and survival. J Clin Invest 1986; 78: 1220–8

    Article  PubMed  CAS  Google Scholar 

  106. Smith PD, Lamerson CL, Wong HL, et al. Granulocyte-macrophage colony-stimulating factor stimulates human monocyte accessory cell function. J Immunol 1990; 144: 3829–34

    PubMed  CAS  Google Scholar 

  107. Grabstein KH, Urdal DL, Tushinski RJ, et al. Induction of macrophage tumoricidal activity by granulocyte-macrophage colony-stimulating factor. Science 1986; 232: 506–8

    Article  PubMed  CAS  Google Scholar 

  108. Chachoua A, Oratz R, Hoogmoed R, et al. Monocyte activation following systemic administration of granulocyte-macrophage colony-stimulating factor. J Immunother Emphasis Tumor Immunol 1994; 15: 217–24

    Article  PubMed  CAS  Google Scholar 

  109. Ragnhammar P, Fagerberg J, Frodin JE, et al. 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 1993; 53: 751–8

    Article  PubMed  CAS  Google Scholar 

  110. Chachoua A, Oratz R, Liebes L, et al. 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 1994; 16: 132–41

    Article  PubMed  CAS  Google Scholar 

  111. Wiltschke C, Krainer M, Wagner A, et al. Influence of in vivo administration of GM-CSF and G-CSF on monocyte cytotoxicity. Exp Hematol 1995; 23: 402–6

    PubMed  CAS  Google Scholar 

  112. Scarffe JH. Emerging clinical uses for GM-CSF. Eur J Cancer 27; 1991: 1493–504

    Article  PubMed  CAS  Google Scholar 

  113. Herrmann F, Schulz G, Lindemann A, et al. Hematopoietic responses in patients with advanced malignancies treated with recombinant human granulocyte-macrophage colony-stimulating factor. J Clin Oncol 1989; 7: 159–67

    PubMed  CAS  Google Scholar 

  114. Schwartz GK, Collins JJ, Galazka A, et al. Phase I study of subcutaneously administered bacterially-synthesised recombinant human granulocyte-macrophage colony-stimulating factor. Eur J Cancer 1992; 28: 470–3

    Article  PubMed  CAS  Google Scholar 

  115. Bartholeyns J, Lombard Y, Dumont S, et al. Immunotherapy of cancer: experimental approach with activated macrophages proliferating in culture. Cancer Detect Prev 1988; 12: 413–20

    PubMed  CAS  Google Scholar 

  116. Chokri M, Freudenberg M, Galanos C, et al. Antitumoral effects of lipopolysaccharides, tumor necrosis factor, interferon and activated macrophages: synergism and tissue distribution. Anticancer Res 1989; 9: 1185–90

    PubMed  CAS  Google Scholar 

  117. Chakraborty NG, Okino T, Stabach P, et al. Adoptive transfer of activated human autologous macrophages results in regression of transplanted human melanoma cells in scid mice. In Vivo 1991; 5: 609–14

    PubMed  CAS  Google Scholar 

  118. Stevenson HG, Keenan AM, Woodhouse C, et al. Fate of IFN-gamma activated killer blood monocytes adoptively transferred into the abdominal cavity of patients with peritoneal carcinoma. Cancer Res 1987; 47: 6100–3

    PubMed  CAS  Google Scholar 

  119. Andreesen R, Picht J, Löhr GW. Primary cultures of human blood-born macrophages grown on hydrophobic teflon membranes. J Immunol Methods 1983; 56: 295–304

    Article  PubMed  CAS  Google Scholar 

  120. Brugger W, Scheibenbogen C, Krause S, et al. Large scale production of human tumor cytotoxic macrophages grown from blood monocytes for the use in adoptive immunotherapy trials. Cancer Detect Prevent 1991; 15: 407–12

    PubMed  CAS  Google Scholar 

  121. Andreesen R, Scheibenbogen C, Krause S, et al. Adoptive transfer of tumor cytotoxic macrophages generated in vitro from circulating blood monocytes: a new approach to cancer immunotherapy. Cancer Res 1990; 50: 7450–6

    PubMed  CAS  Google Scholar 

  122. Andreesen R, Hennemann B. Adoptive immunotherapy with autologous macrophages: current status and future perspectives. Pathobiology 1991; 59: 259–63

    Article  PubMed  CAS  Google Scholar 

  123. Faradji A, Bohbot A, Schmitt-Goguel M, et al. Phase I trial of intravenous infusion of ex-vivo-activated autologous blood-derived macrophages in patients with non—small-cell lung cancer: toxicity and immunomodulatory effects. Cancer Immunol Immunother 1991: 33: 319–26

    Article  PubMed  CAS  Google Scholar 

  124. Faradji A, Bohbot A, Schmitt Goguel M, et al. Apheresiselutriation program for adoptive immunotherapy with autologous activated monocytes in cancer patients. Int J Artif Organs 1991: 14: 304–12

    PubMed  CAS  Google Scholar 

  125. Lopez M, Fechtenbaum J, David B, et al. Adoptive immunotherapy with activated macrophages grown in vitro from blood monocytes in cancer patients: a pilot study. J Immunother 1992; 11: 209–17

    Article  PubMed  CAS  Google Scholar 

  126. Hennemann B, Scheibenbogen C, Schümichen C, et al. Intrahepatic adoptive immunotherapy with autologous tumor cytotoxic macrophages in patients with cancer. J Immunother 1995; 18: 19–27

    Article  CAS  Google Scholar 

  127. Takeda T, Kobyashi T, Monden T, et al. The effect of local immunotherapy for breast cancer using a mixture of OK-432 and fibrinogen supplemented with activated macrophages. Biotherapy 1993; 7: 47–54

    Article  PubMed  CAS  Google Scholar 

  128. Dorsch M, Hock H, Kunzendorf U, et al. Macrophage colonystimulating factor gene transfer into tumor cells induces macrophage infiltration but not tumor suppression. Eur J Immunol 1993; 23: 186–90

    Article  PubMed  CAS  Google Scholar 

  129. Bottazzi B, Walter S, Govoni D, et al. Monocyte chemotactic cytokine gene transfer modulates macrophage infiltration, growth and susceptibility to IL-2 therapy of a murine melanoma. J Immunol 1992; 148: 1280–5

    PubMed  CAS  Google Scholar 

  130. Walter S, Bottazzi B, Govoni D, et al. Macrophage infiltration and growth of sarcoma clones expressing different amounts of monocyte chemotactic protein/JE. Int J Cancer 1991; 49: 431–5

    Article  PubMed  CAS  Google Scholar 

  131. Heike Y, Sone S, Yano S, et al. M-CSF gene transduction in multidrug-resistant human cancer cells to enhance anti-P-glycoprotein antibody-dependent macrophage mediated cytotoxicity. Int J Cancer 1993; 54: 851–7

    Article  PubMed  CAS  Google Scholar 

  132. Dranoff G, Jaffe E, Lazenby A, et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent specific and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA 1993; 90: 3539–43

    Article  PubMed  CAS  Google Scholar 

  133. Blankenstein T, Qin Z, Überla K, et al. Tumor suppression of tumor cell targeted tumor necrosis factor α gene transfer. J Exp Med 1991; 173: 1047–52

    Article  PubMed  CAS  Google Scholar 

  134. Lollini PL, Bosco MC, Cavallo F, et al. Inhibition of tumor growth and enhancement of metastasis after transfection of the gamma-IFN gene. Int J Cancer 1993; 55: 320–9

    Article  PubMed  CAS  Google Scholar 

  135. Haddada H, Lopez M, Martinache C, et al. Efficient adenovirus-mediated gene transfer into human blood monocyte-derived macrophages. Biochem Biophys Res Commun 1993; 195: 1174–83

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Hematology/Oncology, Klinik und Poliklinik für Innere Medizin I, Klinikum der Universität Regensburg, 93042, Regensburg, Germany

    Burkhard Hennemann & Reinhard Andreesen

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  1. Burkhard Hennemann
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Hennemann, B., Andreesen, R. Monocyte/Macrophage Activation by Immunostimulators. Clin. Immunother. 5, 294–308 (1996). https://doi.org/10.1007/BF03259328

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