Skip to main content
Log in

Development of immunotherapeutic strategies for the treatment of malignant neoplasms

  • Published:
Biotherapy

Abstract

Focused preclinical studies have been used to gain insight into the mechanism of therapeutic activity of cytokines, growth factors and biological response modifiers (BRMs). These data can then be used to develop a clinical hypothesis to facilitate the development of these new biological drugs. In this manuscript, we discuss a number of preclinical and clinical studies using interferon-γ, IL-2, and the colony stimulating factors. The importance of the systematic profiling of the biological activity of such biological drugs is emphasized and we discuss the utility of the mechanistic data in their clinical development. The overall preclinical approach identifies the cellular, biochemical or gene regulatory event that is associated with the therapeutic activity of a biologic and this surrogate (be it biological, chemical, or quality of life) is then used to optimize the clinical protocol in a phase lb trial. This, in theory, results in the rapid identification of the optimal dose, schedule and route of administration for subsequent testing in a phase II/III clinical trial.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Oldham RK. Biological response modifiers program. J Biol Response Modif 1982; 1: 81–100.

    Google Scholar 

  2. Talmadge JE, Herberman RB. The preclinical screening laboratory. Evaluation of immunomodulatory and therapeutic properties of biological response modifiers. Can Treat Rep 1986; 70: 171–82.

    Google Scholar 

  3. Oldham RK. Biologicals and biological response modifiers: fourth modality of cancer treatment. Can Treat Rep 1984; 68: 221–32.

    Google Scholar 

  4. Mihich E. Future perspectives for biological response modifiers: a viewpoint. Sem in Onc 1986; 13: 234–54.

    Google Scholar 

  5. Gilis S, Conlon PJ, Cosman D, Hopp TP, Dower SK, Price V, Mochizuki DY, Urdal DL. Lymphokines: from conjecture to the clinic. Sem in Onc 1986; 13: 218–27.

    Google Scholar 

  6. Foon KA. Biological Response Modifiers: The new immunotherapy. Cancer Res 1989; 49: 1621–39.

    Google Scholar 

  7. Talpaz M, Kantarjian HM, McCredie K, Trujillo JM, Keating MJ, Gutterman JV Hematologic remission and cytogenetic improvement induced by recombinant human interferon alpha A in chronic myelogenous leukemia. N Engl J Med 1986; 314: 1065–9.

    Google Scholar 

  8. Horning, SJ, Merigan TC, Krown SE, Gutterman JU,Louie A, Gallagher J, McCravey J, Abramson J, Cabanillas F, Oettgen H, Rosenberg SA. Human interferon alpha in malignant lymphoma and Hodgkin's disease. Cancer (Phila.) 1985; 56: 1305–10.

    Google Scholar 

  9. O'Connell MJ, Colgan JP, Oken MM, Ritts Jr RE, Kay NE and Itri LM. Clinical trial of recombinant leukocyte A interferon as initial therapy for favorable histology non-Hodgkin's lymphomas and chronic lymphocytic leukemia. An Eastern Cooperative Oncology Group pilot study. J Clin Oncol 1986; 4: 128–36.

    Google Scholar 

  10. Misset JL, Mathe G, Gastiaburu J, Goutner A, Dorval T, Gouveia J, Schwarzenberg L, Machover D, Ribaud P, de Vassal F. Treatment of leukemias and lymphomas by interferons: II. phase II of the trial treatment of chronic lymphoid leukemia by human interferon a+. Biomed Pharmacother 1982; 36: 112–6.

    Google Scholar 

  11. Schulof RS, Lloyd MJ, Stallings JJ, Mai D, Phillips TM, Jones GJ, Schechter GP. Recombinant leukocyte A interferon in B-cell chronic lymphocytic leukemia:in vivo effects on autologous antitumor immunity. J Biol Response Mod 1985; 4: 310–23.

    Google Scholar 

  12. Foon KA, Bottino G, Abrams PG. Phase II trial of recombinant leukocyte A interferon in patients with advanced chronic lymphocytic leukemia. Am J Med 1985; 78: 216–20.

    Google Scholar 

  13. Spiegel RJ. The alpha interferons: Clinical overview. Sem in Onc 1987; 14: 1–12.

    Google Scholar 

  14. Golomb HM, Fefer A, Golde DW, Ozer H, Portlock C, Silber R, Rappeport J, Ratain MJ, Thompson J, Bonnem E, Spiegel R, Tensen L, Burke JS, and Vardiman JW. Report of a multi-institutional study of 193 patients with hairy cell leukemia treated with interferon-alfa2b. Sem in Onc 1988; 15: 7–9.

    Google Scholar 

  15. Dorr RT, Salmon SE, Robertone A, Bonnem E. Phase I–II trial of interferon-alb by continuous subcutaneous infusion over 28 days. J Interferon Res 1988; 8: 717–25.

    Google Scholar 

  16. Quesada JR, Reuben J, Manning JT, Hersh E, Gutterman JU. Alpha interferon for induction of remission in hairy-cell leukemia. N Engl J Med 1984; 310: 15–8.

    Google Scholar 

  17. Muss HB, Costanzi JJ, Leavitt R, Williams RD, Kempf RA, Pollard R, Ozer H, Zekan PJ, Grunberg SM, Mitchell MS, Caponera M, Gavigan M, Ernest ML, Venturi C, Greiner J, Spiegel RJ. Recombinant alfa interferon in renal cell carcinoma. A randomized trial of two routes of administration. J Clin Onc. 1987; 5: 286–91.

    Google Scholar 

  18. Leavitt RD, Ratanatharathorn V, Ozer H, Ultmann JE, Portlock C, Myers JW, Kisner D, Norred S, Spiegel RJ, Bonnem EM. a-2b interferon in the treatment of Hodgkin's disease and non-Hodgkin's lymphoma. Semin Oncol 1987; 14: 18–23.

    Google Scholar 

  19. Bunn PA, Idhe DC, Foon KA. The role of recombinant interferon alpha-2a in the therapy of cutaneous T-cell lymphomas. Cancer 1986; 57: 1689–95.

    Google Scholar 

  20. Bunn PA, Foon KA, Ihde DC, Longo DL, Eddy J, Winkler CF, Veach SR, Zeffren J, Sherwin S, Oldham. Recombinant leukocyte A interferon: An active agent in advanced cutaneous T-cell lymphomas. Ann Intern Med 1984; 101: 484–7.

    Google Scholar 

  21. Olsen EA, Rosen ST, Vollmer RT, Variakojis D, Roenigk HH Jr, Diab N, Zeffren J. Interferon a-2a in the treatment of cutaneous T cell lymphoma. J Am Acad Dermatol 1989; 20: 395–407.

    Google Scholar 

  22. Quesada JR, Rios A, Swanson D, Trown P, Gutterman JU. Antitumor activity of recombinant-derived interferon alpha in metastatic renal cell carcinoma. J of Clinical Onc 1985; 3: 1522–8.

    Google Scholar 

  23. Muss HB. Interferon therapy for renal cell carcinoma Sem in Onc 1987; 14: 36–42.

    Google Scholar 

  24. Lane HC, Feinberg J, Davey V, Deyton L, Baseler M, Manischewitz J, Masur H, Kovacs JA, Herpin B, Walker R, Metcalf JA, Salzman N, Quinnan G, Fauci AS. Anti-retro- viral effects of interferon-a in AIDS-associated Kaposi's sarcoma. The Lancet 1988; p. 1218–22.

  25. DeWit R, Boucher CAB, Veenh-ef KHN, Schattenkerk JKME, Bakker PJM, Danner SA. Clinical and virological effects of high-dose recombinant interferon-a in disseminated AIDS-related Kaposi's sarcoma. The Lancet, 1988; p. 1214–17.

  26. Bhalla K, Birkhofer M, Grant S, Graham G. The effect of recombinant human granulocytemacrophage colony stimulating factor (rGM-CSF) on 3′-azido-3′-deoxythymidine (AZT)-mediated biochemcal and cytotoxic effects on normal human myeloid progenitor cells. Exp Hematol 1989; 17: 17–20.

    Google Scholar 

  27. Interferon Alpha Study Group. A randomized placebo-controlled trial of recombinant human interferon alpha 2a in patients with AIDS. J of Acquired Immune Syndromes 1988; 1: 111–8.

    Google Scholar 

  28. Krown SE, Real FX, Vadhan-Raj S, Cunningham Rundles S, Krim M, Wong G, Oettgen HF. Kaposi's sarcoma and the acquired immune dificiency syndrome. Treatment with recombinant interferon alpha and analysis of prognostic factors. Cancer (Phila.) 1986; 57: 1662–5.

    Google Scholar 

  29. Rios A, Mansell P, Newell GR, Reuben JM, Hersh EM, Gutterman JU. Treatment of acquired immunodeficiency syndrome-related Kaposi's sarcome with lymphoblastoid interferon. J Clin Oncol 1985; 3: 506–12.

    Google Scholar 

  30. Groopman JE, Gottlieb MS, Goodman J, Mitsuyasu RT, Conant MA, Prince H, Fahey JL, Derezin M, Weinstein WM, Casavante C, Rothman J, Rudnick S, Volberding PA. Recombinant a-2 interferon therapy for Kaposi's sarcoma associated with the acquired immunodeficiency syndrom. Annals of Internal Med 1984; 100: 671–6.

    Google Scholar 

  31. Torti FM, Shortliffe LD, Wiliams RD, Pitts WC, Kempson RL, Ross JC, Palmer J, Meyers F, Ferrari M, Hannigan J, Spiegel R, McWhirter K, Freiha F. Alpha interferon in superficial bladder cancer: a Northern California Oncology Group Study. J Clin Oncol 1988; 6: 476–83.

    Google Scholar 

  32. Ikic D, Maricic Z, Oresic V, Rode B, Nola P, Smudj K, Knezevic M, Jusic D, Soos E. Applications of human leucocyte interferon in patients with urinary bladder papillomatosis, breast cancer and melanoma. Lancet, 1981; 1: 1022–4.

    Google Scholar 

  33. Scorticatti CH, de la Pena NC, Bellora OG, et al. Systemic IFN-a treatment of multiple bladder papilloma grade I or II patients: pilot study. J Interferon Res 1982; 2: 339–43.

    Google Scholar 

  34. Isaacs A, Lindenman J. Virus interference. 1. The interferons. Proc R Soc Lond B Biol Sci. 1957; 147: 258–67.

    Google Scholar 

  35. Cantell K, Hirvonen S. Preparation of human leukocyte interferon for clinical use. Tex Rep Biol Med 1977; 35: 138–44.

    Google Scholar 

  36. Moormeier J, Ratain M, Westbrook C, Vardiman J, Daly K, Golomb HM. Low dose interferon in the treatment of hairy cell leukemia. Proc Am Assoc Cancer Res 1988; 29: 215.

    Google Scholar 

  37. Jones GJ, Itri LM. Safety and tolerance of recombinant interferon alfa-2a (Roferon-A) in cancer patients. Cancer 1986; 57: 1709–15.

    Google Scholar 

  38. Salmon SE, Durie BGM, Young L, Liu RM, Trown PW, Stebbing N. Effects of cloned human leukocyte interferons in the human tumor stem cell assay. J Clin Oncol 1983; 1: 217–25.

    Google Scholar 

  39. Teichmann JV, Sieber G, Ludwig WD, Ruehl H. Modulation of immune functions by long-term treatment with recombinant interferon-a2 in a patient with hairy-cell leukemia. J of Interferon Res 1988; 8: 15–24.

    Google Scholar 

  40. Edwards BS, Merritt JA, Fuhlbrigge RC, Borden EC. Kinetics of natural cytotoxicity in patients treated with human fibroblast interferon. CII 1981; 11: 1–6.

    Google Scholar 

  41. Maluish AE, Ortaldo JR, Conlon JC, Sherwin SA, Leavitt R, Strong DM, Weirnik P, Oldham RK, Herberman RB. Depression of natural killer cytotoxicity afterin vivo administration of recombinant leukocyte interferon. J of Imm 1983; 37: 236–44.

    Google Scholar 

  42. Knight P. Non-protein engineering: small drug design. Biotechnology 1990; 8: 105.

    Google Scholar 

  43. Langer R. New methods of drug delivery. Science 1990; 249: 1527.

    Google Scholar 

  44. Freidinger RM. Non-peptide ligands for peptide receptors. TIPS 1989; 10: 270.

    Google Scholar 

  45. Hryniuk W, Bush H. The importance of dose intensity in chemotherapy of metastatic breast cancer. (Review) J of Clin One 1984; 2: 1281–8.

    Google Scholar 

  46. Hryniuk W, Levine MN. Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol 4: 1162–1167, 1986.

    Google Scholar 

  47. Griswold Jr DP, Trader MW, Frei III E, Peters WP, Wolpert MK, Laster Jr WR. Response of drug-sensitive and -resistant L1210 leukemias to high-dose chemotherapy. Cancer Res 1987; 47: 2323–8.

    Google Scholar 

  48. Tannock IF, Boyd NF, DeBoer G, Erlichman C, Fine S, Larocque G, Mayers C, Perrault D, Sutherland H. A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer. J of Clin Onc 1988; 6: 1377–87.

    Google Scholar 

  49. Herberman RB. Design of clinical trials with biological response modifiers. Can Trmt Reports 1985; 69: 1161–4.

    Google Scholar 

  50. Jaffe HS, Herberman RB. Rationale for recombinant human IFN-a adjuvant immunotherapy for cancer. (Editorial) J NCI 1988; 80: 616–9.

    Google Scholar 

  51. Talmadge JE, Tribble HR, Pennington RW, Phillips H, Wiltrout RH. Immunomodulatory and immunotherapeutic properties of recombinant gamm interferon and recombinant tumor necrosis factor in mice. Cancer Res 1987; 47: 2563–70.

    Google Scholar 

  52. Black PL, Phillips H, Tribble HR, Pennington R, Schneider M, Talmadge JE. Correlation of immunomodulatory and therapeutic activities of interferon and interferon inducers in metastatic disease. J of Cell Biochemistry 1988; 36: 377–92.

    Google Scholar 

  53. Maluish AE, Urba WJ, Longo DLO, Overton WR, Coggin D, Crisp ER, Williams R, Sherwin SA, Gordon K, Steis RG. The determination of an immunologically active dose of interferon-gamma in patients with melanoma. J Clin Oncol 1988; 6: 434–45.

    Google Scholar 

  54. Kleinerman ES, Kurzrock R, Wyatt D, Quesado JR, Gutterman JU, Fidler IJ. Activation or supression of the tumoricidal properties of monocytes from cancer patients following treatment with human recombinant q-interferon. Can Res 1986; 46: 5401–5.

    Google Scholar 

  55. Thompson JA, Cox WW, Lindgren CG, Collins C, Neraas KA, Bonnem EM, Fefer A. Subcutaneous recombinant gamma interferon in cancer patients: toxicity, pharmacokinetics, and immunomodulatory effects. Cancer Immunology & Immunotherapy 1987; 25: 47–53.

    Google Scholar 

  56. Aulitzky W, Gastl G, Aulitzky WE, Nachbaur K, Lanske B, Kemmler G, Flener R, Frick J, Huber C. Interferon-g for the treatment of metastatic renal cancer: Dose-dependent stimulation and downregulation of beta-2 microglobulin and neopterin responses. Immunobiol 1987; 176: 85–95.

    Google Scholar 

  57. Killion JJ, Fidler IJ. The biology of tumor metastasis. Seminars in Onc 1989; 16: 106–15.

    Google Scholar 

  58. Talmadge JE, Fidler IJ, Oldham RK. Screening for biological response modifiers: methods and rationale. Dordrecht: Martinus Nijhoff Publ, 1985; 1–193.

    Google Scholar 

  59. Talmadge JE, Phillips H, Schindler J, Tribble H, Pennington R. Systematic preclinical study on the therapeutic properties of recombinant human interleukin-2 for the treatment of metastatic disease. Can Res 1987; 47: 5725–32.

    Google Scholar 

  60. Sano T, Saijo N, Sasaki Y, Shinkai T, Eguchi K, Tamura T, Sakurai M, Takahashi H, Nakano H, Nakagawa K, Hong W-S. Three schedules of recombinant human interleukin-2 in the treatment of malignancy: Side effects and immunologic effects in relation to serum level. Jpn J Can Res (Gann) 1988; 79: 131–43.

    Google Scholar 

  61. Mottel CG. On lymphokines, cytokines and breakthroughs. JAMA 1986; 256: 1341.

    Google Scholar 

  62. Konrad MW, Hamstreet, G, Hersh, EM, Mansell PWA, Mertelsmann R, Kolitz JE, Bradley, EC. Pharmacokinetics of recombinant interleukin-2 in humans. Cancer Res. 1990; 50: 2009.

    Google Scholar 

  63. Thompson JA, Lee DJ, Lindgren CG, Benz LA, Collins C, Levitt D, Fefer A. Influence of dose and duration of infusion of interleukin-2 on toxicity and immunomodulation. J. Clin Conc 1988; 6: 669–78.

    Google Scholar 

  64. Alper J. Cetus' proleukin in cancer — the excitement grows. SCRIP 1988; 1363: 24.

    Google Scholar 

  65. Oldham O, Maleckar J, West W, and Yannelli J. IL-2 and Cellular Therapy: Lymphokine activated killer cells and tumor-derived activated cells. In: Preund, Link, Welde, eds. Cytokines in Hemopoiesis, Oncology and AIDS. Berlin, Heidelberg: Springer-Verlag, 1990; 661–71.

    Google Scholar 

  66. Ghosh AK, Dazzi H, Thatcher N, Moore M. Lack of correlation between peripheral blood lymphokine-activated killer (LAK) cell function and clinical response in patients with advanced malignant menaloma receiving recombinant interleukin 2. Int J Cancer 1989; 43: 410–4.

    Google Scholar 

  67. Anderson TM, Irayashi Y, Tokuda Y, Colquhoun SD, Carmack Holmes E, Golub SH. Effects of systemic recombinant interleukin 2 on natural killer and lymphokine-activated killer activity of human tumor infiltrating lymphocytes. Cancer Res 1988; 48: 1180–3.

    Google Scholar 

  68. Ettinghausen SE, Lipford EH, Mule JJ, Rosenberg SA. Recombinant interleukin 2 stimulates in vivo proliferation of adoptively transferred lymphokine-activated killer (LAK cells. J Immunol 1985; 135: 3623–35.

    Google Scholar 

  69. Lotze MT, Chang AE, Seipp CA, Simpson C, Vetto SJ, Rosenberg SA. High-dose recombinant interleukin 2 in the treatment of patients with disseminated cancer. Responses, treatment-related morbidity and histologic findings. J Amer Med Assoc 1986; 256: 3117–24.

    Google Scholar 

  70. Heo DS, Whiteside TL, Johnson JT, Chen K, Barnes EL, Herberman RB. Long-term interleukin-2-dependent growth and cytotoxic activity of tumour-infiltrating lymphocytes from human squamous cell carcinomas of the head and neck. Cancer Res. 1987; 47: 6353–62.

    Google Scholar 

  71. Ettinghausen SE, Lipford III EH, Mule JJ, Rosenberg SA. Systemic administration of recombinant interleukin 2 stimulatesin vivo lymphoid cell proliferation in tissues. J Immunol 1985; 135: 1488–97.

    Google Scholar 

  72. Herberman R.B. Clinical Cancer Therapy with IL-2, Cancer Investigation 1989: 7; 515–6.

    Google Scholar 

  73. Roth AD, Kirkwood JM. New clinical trials with interleukin-2: Rationale for regional administration. Nat. Immun. Cell Growth Regul. 1989; 8: 153.

    Google Scholar 

  74. Lotze MT, Custer MC, Rosenberg SA. Intraperitoneal administration of interleukin-2 in patients with cancer. Archs. Surg. 1986; 121: 1373.

    Google Scholar 

  75. Pizza GC, Severini G, Menniti D, DeVinci C, Corrado F. Tumor regression after intralesional injection of interleukin-2 (IL-2) in bladder cancer: preliminary report. Int J Cancer 1984; 34: 359.

    Google Scholar 

  76. Pulley MS, Edwards JM, Wolstencroft RA, Dumonde DC. Endolymphatic administration of buffy-coat interleukin in patients with malignant melanoma. Proc. Br. As. Cancer Res. 1988; 60: A46.

    Google Scholar 

  77. Forni G, Cavillo GP, Giovarelli, M Benetton G, Jemma C, Barioglio MG DeStenfani A, Forni M, Santoni A, Modesti A, Cavallo G, Menzio P, Cortesina G. Tumor immunotherapy by the local injection of interleukin-2 and non-reactive lymphocytes: experimental and clinical results. In: Cruse, Lewis, Prog. Exp. Tumor Res. Vol. 32, p. 187 (Karger, Basel 1988).

    Google Scholar 

  78. Crum ED, Kaplan DR.In vivo activity of solid phase interleukin 2. Cancer Res 1991; 51: 875.

    Google Scholar 

  79. Fujjwara T, Sakagami K, Matsuoka J, Shiozaki S, Uchida S Fujioka K, Takada Y, Onoda T, Orita K. Application of an interleukin 2 slow delivery system to the immunotherapy of established murine colon 26 adenocarcinoma liver metastases. Cancer Res 1990; 50: 7003.

    Google Scholar 

  80. Herberman RB. Interleukin-2 Therapy of Human Cancer: Potential benefits verses toxicity. J of Clin Oncology 1989; 7: 1–4.

    Google Scholar 

  81. Clark JW, Smith II JW, Steis RRG, Urba WJ, Crum E, Miller R, McKnight J, Beman J, Stevenson HC, Creekmore S, Stewart M, Conlon K, Sznol M, Kremers P, Cohen, Longo DL. Interleukin, 2 and Lymphokine activated killer cell therapy: Analysis of a bolus interleukin 2 and a continuous infusion interleukin 2 regimen. Cancer Res 1990; 50: 7343–50.

    Google Scholar 

  82. West WH, Tauer KW, Yannelli JR, Marshall GD, Orr DW, Thurman GB, Oldham RK. Constant-infusion recombinant interleukin-2 plus lymphokine-activated killer cells in metastatic renal cancer. N Eng J Med 1987; 316: 895–905.

    Google Scholar 

  83. Oldham R, Maleckar J, West W, Yannelli J. IL-2 and cellular therapy: Lymphokine-activated killer cells and tumor-derived aactivated cells. p. 661. Cytokines in Hematopoiesis, Oncology, and AIDS eds. Freund/Link/Welte Springer-Verlag, Berlin 1990.

    Google Scholar 

  84. Sosman JA, Kohler PC, Hank JA, Moore KH, Bechhofer R, Storer B, Sondel PM. Repetitive weekly cycles of interleukin-2. II. Clinical and immunologic effects of dose, schedule, and addition of indomethacin. J Natl Cancer Inst 80: 1451–61, 1988.

    Google Scholar 

  85. Creekmore SP, Harris JE, Ellis TM, Braun DP, Cohen II, Bhoopalam N, Jassak PF, Cahill MA, Canzoneri CL, Fisher RI. A phase I clinical trial of recombinant interleukin-2 by periodic 24-hour intravenous infusions. J Clin Onc 1989; 7: 276–84.

    Google Scholar 

  86. Sondel PM, Kohler PC, Hank JA, Moore KH, Rosenthal NS, Sosman JA, Bechhofer R, Storer B. Clinical and immunological effects of recombinant interleukin 2 given by repetitive weekly cycles to patients with cancer. Can Res 1988; 48: 2561–7.

    Google Scholar 

  87. Mitchell MS, Kempf RA, Harel W, Shau H, Boswell WD, Lind S, Bradley EC. Effectiveness and tolerability of low-dose cyclophosphamide and low-dose intravenous interleukin-2 disseminated melanoma. J Clin Onc 1988; 6: 409–24.

    Google Scholar 

  88. Kolitz JE, Wong GY, Welte K, Merluzzi VJ, Engert A, Bialas T, Polivka A, Bradley EC, Konrad M, Gnecco C, Oettgen HF, and Mertelsmann R. Phase I trial of recombinant interleukin-2 and cyclophosphamide: augmentation of cellular immunity and T-cell mitogenic response with long-term administration of rIL-2. J Biological Response Modifiers 1988; 7: 457–72.

    Google Scholar 

  89. Coffman FD, Green LM, Ware CF. The relationship of receptor occupancy to the kinetics of cell death mediated by tumor necrosis factor. Lymphokine Res 4, 1988, p 371–83.

    Google Scholar 

  90. Shadduck RK, Waheed A, Wing EJ. Demonstration of a Blood-Bone Marrow barrier to macrophage colony stimulating factor. Blood 1989; 73: 68–73.

    Google Scholar 

  91. Chen BD-M.In vivo administration of recombinant human interleukin-q and macrophage colony stimulating factor (M-CSF) induce a rapid loss of M-CSF receptors in mouse bone marrow cells and peritoneal macrophages: effect of administration route. Blood 1991; 77: 1923.

    Google Scholar 

  92. Griffin, JD. Editorial: Hemopoietins in oncology: factoring out myelosuppression J Clin Onc 1989; 7: 151–5.

    Google Scholar 

  93. Editorial: More is better. J Clin Conc 1988; 6: 1365-7.

  94. Antman KS, Griffin JD, Elias A, Socinski MA, Ryan L, Cannistra SA, Oette D, Whitley M, Frei III E, Schnipper LE. Effect of recombinant human granulocyte-macrophage colony-stimulating factor of chemotherapy-induced myelosuppression. The New Eng J of Med 1988; 319: 593–8.

    Google Scholar 

  95. Ulich Tr, Castillo J, Watson LR, Yin S, Garnick MB.In vivo hematologic effects of recombinant effects of recombinant human macrophage colony stimulating factor. Blood 1991; 75: 846.

    Google Scholar 

  96. Hoelzer D, Ganser A, Volkers B, Greher J, Walther F.In vitro andin vivo action of recombinant human gm-CSF (rhGM-CSF) in patients with myelodysplastic syndromes. Blood Cells 1988; 14: 551–9.

    Google Scholar 

  97. Groopman JE, Mitsuyasu RT, DeLeo MJ, Oette DH, Golde DW. Effect of recombinant human granulocyte macrophage colony-stimulating factor on myelopoiesis in the acquired immunodeficiency syndrome. N Eng J Med 1988; 317: 593–8.

    Google Scholar 

  98. Brandt SJ, Peters WP, Atwater SK, Kurtzberg J, Borowitz MJ, Jones RB, Shpall EJ, Bast Jr., RC, Gilbert CJ, Oette DH. Effect of recombinant human granulocyte-macrophage colony-stimulating factor on hematopoiesic reconstitution after high-dose chemotherapy and autologous bone marrow transplantation. The New Eng J of Med 1988; 318: 869–75.

    Google Scholar 

  99. Ganser A, Volkers B, Greher B, Ottmann OG, Walther F, Becher R, Bergmann L, Schulz G, Hoelzer D. Recombinant human granulocyte-macrophage colony stimulating factor in patients with myelodysplastic syndromes-A Phase I/II trial. Blood 1989; 73: 31–7.

    Google Scholar 

  100. Vadhan-Raj S, Buescher S, LeMaistre A, Keating M, Walters R, Ventura C, Hittelman W, Broxmeyer HE, Gutterman JU. Stimulation of hematopoiesis in patients with bone marrow failure and in patients with malignancy by recombinant human granulocyte-macrophage colony stimulating factor. Blood 1988; 72: 134–41.

    Google Scholar 

  101. Steward WP, Scharffe JH, Austin R, Bonnem E, Thatcher N, Morgenstern G, Crowther D. Recombinant human granulocyte macrophage colony stimulation factor (rhGM-CSF) given as daily short infusions — a phase I dose-toxicity study. Behring Inst Mit 1988; 83: 324–6.

    Google Scholar 

  102. Kaplan SS, Basford RE, Wing EJ, Shadduck RK. The effect of recombinant human granulocyte macrophage colony-stimulating factor on neutrophil activation in patients with refractory carcinoma. Blood 1989; 73: 636–38.

    Google Scholar 

  103. Vadhan-Raj S, Buescher S, Broxmeyer HE, LeMaistre A, Lepe-Zuniga JL, Ventura G, Jeha S, Horwitz LJ, Trujillo JM, Gillis S, Hittelman WN, Gutterman JU. Stimulation of myelopoiesis in patients with a plastic anemia by recombinant human granulocyte-macrophage colony-stimulating factor. New Eng J of Med 1988; 319: 1628–34.

    Google Scholar 

  104. Socinski MA, Elias A, Schnipper L, Cannistra SA, Antman KH, Griffin JD. Granulocyte-macrophage colony stimulating factor expands the circulating haemopoietic progenitor cell compartment in man. The Lancet May 1988; 28: 1194–8.

    Google Scholar 

  105. Gutterman J. Clinical studies of granulocyte macrophage colony stimulating factor. Sem in Onc 1988; 15: 52–3.

    Google Scholar 

  106. Baldwin GC, Gasson JC, Quan SG, Fleischmann J,Weisbart R, Oette D, Mitsuyasu RT, Golde DW. Granulocyte-macrophage colony-stimulating factor enhances neutrophil function in acquired immunodeficiency syndrome patients. Proc Natl Acad Sci USA, 1988: 85: 2763–6.

    Google Scholar 

  107. Herrmann F, Schulz G, Lindemann A, Meyenburg W, Oster W, Krumwieh D, Mertelsmann R. Hematopoietic responses in patients with advanced malignancy treated with recombinant human granulocyte-macrophage colony-stimulating factor. J Clin Onc 1989; 7: 159–67.

    Google Scholar 

  108. Kodo H, Tajika K, Takahashi S, Ozawa K, Asano S, Takaku F. Acceleration of neutrophilic granulocyte recovery after bone-marrow transplantation by administration of recombinant human granulocyte colony-stimulating factor. The Lancet 1988; 2: 38–9.

    Google Scholar 

  109. Gabrilove JL, Jakubowski A, Scher H, Sternberg C, Wong G, Grous J, Yagoda A, Fain K, Moore MAS, Clarkson B, Oettgen HF, Alton K, Welte K, Souza L. Effect of granulocyte colony-stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of the urothelium. New Eng J Med 1988; 318: 1414–22.

    Google Scholar 

  110. Duhrsen U, Villeval J-L, Boyd J, Kannourakis G, Morstyn G, Metcalf D. Effects of recombinant human granulocyte colony-stimulating factor on hematopoietic progenitor cells in cancer patients. Blood 1988; 72: 2074–81.

    Google Scholar 

  111. Bronchud MH, Potter MR, Morgenstern G, Blasco MJ, Scarff JH, Thatcher N, Crowther D, Souza LM, Alton NK, Testa NG, Dexter TM.In vitro andin vivo analysis of the effects of recombinant human granulocyte colony-stimulating factor in patients. Br J Cancer 1988; 58: 64–9.

    Google Scholar 

  112. Glaspy JA, Baldwin GC, Robertson PA, Souza L, Vincent M, Ambersley J, Golde DW. Therapy for neutropenia in hairy cell leukemia with recombinant human granulocyte colony-stimulating factor. Annals of Int Med 1988; 109: 789–805.

    Google Scholar 

  113. Morstyn G, Souza LM, Keech J, Sheridan W, Campbell L, Alton NK, Green M, Metcalf D, Fox R. Effect of granulocyte colony stimulating fator on neutropenia induced by cytotoxic chemotherapy. The Lancet 1988; 26: 667–71.

    Google Scholar 

  114. Komiyama A, Ishiguro A, Kubo T, Matsuoka T, Yasukohchi S, Yasui K, Yanagisawa M, Yamada S, Yamazaki M, Akabane T. Increases in neutrophil counts by purified human urinary colony-stimulating factor in chronic neutropenia of childhood. Blood 1988; 71: 41–5.

    Google Scholar 

  115. Motoyoshi K, Takaku F, Miura Y. High serum colony stimulating activity of leukocytopenic patients after in travenous infusions of human urinary colony-stimulating factor. Blood 1983; 62: 685–8.

    Google Scholar 

  116. Masaoka T, Motoyoshi K, Takaku F, Kato S, Harada M, Kodera Y, Kanamaru A, Moriyama Y, Ohno R, Ohira M, Shibata H, Inoue T. Administration of human urinary colony stimulating factor after bone marrow transplantation. Bone Marrow Transplantation 1988; 3: 121–7.

    Google Scholar 

  117. Plunda JM, Yarchoan R, Smith PD, McAtee N, Shay LE, Otte D, Maha M, Wahl SM, Myers CE, Broder S. Subcutaneous recombinant granulocyte-macrophage colony stimulating factor used as a single agent and in an alternating regimen with azidothymidine in leukopenic patients with severe human immunodeficiency virus infection. Blood 1990; 76: 463.

    Google Scholar 

  118. Mitsyasu R, Levine J, Miles SA, DeLeo M, Oette D, Golde D, Groopman J. Effects of long term subcutaneous administration of GM-CSF in patients with HIV related leukopenia. Blood 1988; 72: 1336 (abstract supplement).

    Google Scholar 

  119. Merz B. Trials of colony stimulating factors grow, so do applications, side effects. JAMA 1988; 260: 3555.

    Google Scholar 

  120. Wing EJ, Magee DM, Whiteside T, Kaplan SS, Shadduck RK. Recombinant human granulocyte/macrophage colony-stimulating factor enhances monocyte cytotoxicity and secretion of tumor necrosis factor a and interferon in cancer patients. Blood 1989; 73: 643–6.

    Google Scholar 

  121. Kleinerman ES, Knowles RD, Lachman LB, Gutterman U. Effect of recombinant granulocyte/macrophage colony-stimulating factor on human monocyte activityin vitro and following intravenous administration. Cancer Research 1988; 48: 2604–9.

    Google Scholar 

  122. Cebon J, Dempsey P, Fox R, Kannourakis G, Bonnem E, Burgess AW, Morstyn G. Pharmacokinetics of human granulocyte-macrophage colony-stimulating factor using a sensitive immunoassay. Blood 1988; 72: 1340–7.

    Google Scholar 

  123. Herrmann F, Schulz G, Lindemann A, Meyenburg W, Oster W, Krumwieh D, Mertelsmann R. Yeast expressed granulocyte-macrophage colony-stimulating factor in cancer patients: A phase Ib clinical study. Behring Inst. Mitt 1988; 83: 107–18.

    Google Scholar 

  124. Mirifkin RM, Hersh EM, Salmon SE. A Phase I study of therapy with recombinant granulocyte-macrophage colony-stimulating factor administered by IV bolus or continuous infusion. Behring Inst. Mitt 1988; 83: 125–33.

    Google Scholar 

  125. Chen SA, Shalaby MR, Crase DR, Palladino Jr MA, Baughman RA. Pharmacokinetics of recombinant murine interferon-q and human interferon-aA/D(Ggl) administered in concert and their influence on natural killer cell function in mice. J Interferon Res 1988; 8: 597–608.

    Google Scholar 

  126. Kondo H, Tanaka N, Naomoto Y, Orita K. Antitumor effect of recombinant human interferon-β and interferon-q in combination against human colon cancer cell linein vitro and in nude mice. Jpn J Cancer Res 1987; 78: 1258–65.

    Google Scholar 

  127. Quesada JR, Evans L, Saks SR, Gutterman JU. Recombinant interferon alpha and gamma in combination as treatment for metastatic renal cell carcinoma. J Biological Response Modifiers 1988; 7: 234–9.

    Google Scholar 

  128. Foon K, Doroshow J, Bonnem E, Fefer A, Graham S, Grosh B, Narayan P, Elias L, Harvey H, Schulof R, Williams R, Rinehart J, Zekan P, Catalona W, Dillman R, Salmon S, Galasso F. A prospective randomized trial of a2B-interferonlq-interferon or the combination in advanced metastatic renal cell carcinoma. J Biological Response Modifiers 1988; 7: 5540–5.

    Google Scholar 

  129. Kloke O, Becher R, Niederle N. Response to the combined administration of interferons alpha and gamma after failure of single interferon therapy in chronic myelogenous leukemia. Blut 1987; 55: 453–8.

    Google Scholar 

  130. Schiller JH, Storer B, Bittner G, Willson JKV, Borden EC. Phase II trial of a combination of interferon-Bser and interferon-q in patients with advanced malignant melanoma. J Interferon Res 1988; 8: 581–9.

    Google Scholar 

  131. Kurzrock R, Rosenblum MG, Quesada JR, Sherwin SA, Itri LM, Gutterman JU. Phase I study of a combination of recombinant interferon-alpha and recombinant interferon-gamma in cancer patients. J Clinical Onc. 1986; 4: 1677–83.

    Google Scholar 

  132. Gomez C, LaBanda F, Perres JC, Mora I, Andres A, Bartolome J, Quiroga JA, Gutiez J, Castillo I, Bas C, Armenteros E, Ibarra MZ, Carreno V. Combined recombinant alpha and gamma interferon treatment of chronic hepatitis B virus infection. J Med Virol 1987; 21: A127–8.

    Google Scholar 

  133. Carreno V, Mora I. Combination of recombinant interferons alpha and gamma in treatment of chronic hepatitis B. The Lancet 1987; 7: 1086.

    Google Scholar 

  134. Flodgren P, Malmstrom P, Axelsson B, Boketoft A, Borgstrom S, Sjogren H. Immune functions in melanoma patients during treatment with interferon [HuIFN-a(Le)] alone or in combination with cimetidine. Anticancer Res 1985; 5: 197–204.

    Google Scholar 

  135. Steiner A, Wolf C, Pehamberger H. Comparison of the effects of three different treatment regimens of recombinant interferons (r-IFN-a, r-IFN-a, and r-IFN a + cimetidine) in disseminated malignant melanoma. J Cancer Res Clin Oncol 1987; 113: 459–65.

    Google Scholar 

  136. Cameron RB, McIntosh JK, Rosenberg SA. Synergistic antitumor effects of combination immunotherapy with recombinant interleukin-2 and a recombinant hybrid a-interferon in the treatment of established murine hepatic metastases. Cancer Research 1988; 48: 5810–7.

    Google Scholar 

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

    Google Scholar 

  138. Krigel RL, Padavic-Shaller KA, Rudolph AR, Litwin S, Konrad M, Bradley EC, Comis RL. A Phase I study of recombinant interleukin 2 plus recombinantβ-interferon. Cancer Research 1988; 48: 3875–81.

    Google Scholar 

  139. Tamura T, Sasaki Y, Shinkai T, Eguchi K, Sakurai M, Fujiwara Y, Nakagawa K, Minato K, Bungo M, Saijo N. Phase I study of combination therapy with interleukin 2 andβ-interferon in patients with advanced malignancy. Cancer Research 1989; 49: 730–5.

    Google Scholar 

  140. Agah R, Malloy B, Sherrod A, Bean P, Girgis E, Mazumder A. Therapy of disseminated NK-resistant tumor by the synergistic effects of recombinant interleukin-2 and tumor necrosis factor. J Biological Response Modifers 1988; 7: 140–51.

    Google Scholar 

  141. McIntosh JK, Mule JJ, Merino MJ, Rosenberg SA. Synergistic antitumor effects of immunotherapy with recombinant interleukin-2 and recombinant tumor necrosis factor-a. Cancer Research 1988; 48: 4011–7.

    Google Scholar 

  142. Agah R, Malloy B, Sherrod A, Mazumder A. Successful therapy of natural killer-resistant pulmonary metastases by the synergism of q-interferon with tumor necrosis factor and interleukin-2 in mice. Cancer Research 1988; 48: 2245–8.

    Google Scholar 

  143. Talmadge JE, Tribble HR, Pennington RW, Phillips H, Wiltrout RH. Immunomodulatory and immunotherapeutic properties of recombinant g-interferon and recombinant tumor necrosis factor in mice. Cancer Research 1987; 47: 2563–70.

    Google Scholar 

  144. Shah P, van der Meide PH, Borman T, Schroeder N, Bliss JM, Coombes RC. Effect of human incombinant tumour necrosis factor and rat gamma interferon on nitrosomythylurea-induced mammary tumours. Br J Cancer 1989; 59: 206–9.

    Google Scholar 

  145. McIntosh JK, Mule JJ, Krosnick JA, Rosenberg SA. Combination cytokine immunotherapy with tumor necrosis factor a, interleukin 2, and a-interferon and its synergistic antitumor effects in mice. Cancer Research 1989; 49: 1408–14.

    Google Scholar 

  146. Jakubowski A, Larchian W, Starnes F, Casper E, Begas A, Fain K, Jaffe H, Old L, Oettgen H, Gabrilove J. Phase I trial of intravenous tumor necrosis factor plus interferon-g in patients with advanced cancer. Proc Am Soc Clin Oncol 1988; 7: 164.

    Google Scholar 

  147. Abbruzzese JL, Levin B, Ajani JA, Faintuch JS, Saks S, Patt YZ, Edwards C, Ende K, Gutterman JU. Phase I trial of recombinant human g-interferon and recombinant human tumor necrosis factor in patients with advanced gastrointestinal cancer. Cancer Research 1989; 49: 4057–61.

    Google Scholar 

  148. Scheurich P, Thoma B, Ucer U, Pfizenmaier K. Immunoregulatory activity of recombinant human tumor necrosis factor (TNF)-a. Induction of TNF receptors on human T cells and TNF-a-mediated enhancement of T cell responses. J Immunol 1987; 138: 1786–90.

    Google Scholar 

  149. Lee JC, Truneh A, Smith MF Jr, Tsang KY. Induction of interleukin 2 receptor (TAC) by tumor necrosis factor in YT cells. J Immunol 1987 139: 1935–8.

    Google Scholar 

  150. Owen-Schaub LB, Gutterman JU, Grimm EA. Synergy of tumor necrosis factor and interleukin 2 in the generation of human lymphokine-activated killer cell activity. Cancer Res 1988; 48: 788–92.

    Google Scholar 

  151. Chouaib S, Bertoglio J, Blay J-Y, Marchiol-Fournigault C, Fradelizi D. Generation of lymphokine-activated killer cells: Synergy between tumor necrosis factor and interleukin 2. Proc Natl Acad Sci USA 1988; 85: 6875–79.

    Google Scholar 

  152. Kedar E, Ben-Aziz R, Epstein E, Leshem B. Chemoimmunotherapy of murine tumors using interleukin-2 (IL-2) and cyclophosphamide. Cancer Immunology Immunotherapy 1989; 29: 74–8.

    Google Scholar 

  153. Buckley NJ, Walther PJ, Das AK, Poulton SHM. Schedule-dependent enhanced lethality with combined administration of actinomycin D and tumor necrosis factor in mice. JBRM 1989; 8: 287–96.

    Google Scholar 

  154. Old LJ. Tumor necrosis factor (TNF). Science 1985; 230: 630–2.

    Google Scholar 

  155. Alexander RB, Nelson WG, Coffey DS. Synergistic enhancement by tumor necrosis factor ofin vivo cytotoxicity from chemotherapeutic drugs targeted at DNA topoisomerase II. Cancer Res 1987; 47: 2403–6.

    Google Scholar 

  156. Darzynkiewicz Z, Carter SP, Old LJ. Effect of recombinant tumor necrosis factor on HL-60 cells: cell-cycle specificity and synergism with actinomycin D. J Cell Physiol 1987; 130: 328–35.

    Google Scholar 

  157. Das AK, Buckley NJ, Poulton SHM, Walther PJ. Recombinant human tumor necrosis factor alone and with chemotherapeutic agents. Effect on nude-mouse supported human bladder cancer heterografts. Arch Surg 1989; 124: 107–10.

    Google Scholar 

  158. Salup R, Bock TC, Wiltrout RH. Successful treatment of advanced murine renal cell carcinoma by biocompartmental adoptive chemoimmunotherapy. J Immunol 1987; 138: 641–7.

    Google Scholar 

  159. Black PL, Phillips H, Tribble HR, Pennington RW, Schneider M, Talmadge JE. Correlation of immunomodulatory and therapeutic activities of interferon and interferon inducers in metastatic disease. J Cell Biochem 1988; 36: 377–92.

    Google Scholar 

  160. Hawrylowicz CM, Rees RC, Hancock BW, Potter CW. Depressed spontaneous natural killing and interferon augmentation in patients with malignant lymphoma. Eur J Cancer Clin Oncol 1982; 18: 1081–8.

    Google Scholar 

  161. Maluish AE, Ortaldo JR, Conlon JC, Sherwin SA, Leavitt R, Strong DM, Wiernik P, Oldham RK, Herberman RB. Depression of natural killer cytotoxicity afterin vivo administration of recombinant leukocyte interferon. J Immunol 1983: 131; 503–7.

    Google Scholar 

  162. Talmadge JE, Jaluish AE, Collins M, Schneider M, Herberman RB, Oldham RK, Wiltrout RH. Immunomodulation and antitumor effects of MVE-2 in mice. J Biol Resp 1984; 3: 634–52.

    Google Scholar 

  163. Brunda MJ, Rosenbaum D, Sterm L. Inhibition of experimentally-induced murine metastases by recombinant alpha interferon: correlation between the modulatory effect of interferon treatment on natural killer cell activity and inhibition of metastases. Int J Cancer 1984; 34: 421–6.

    Google Scholar 

  164. Talmadge JE, Adams J, Phillips H, Collins M, Lenz B, Schneider M, Schlick E, Ruffman R, Wiltrout RH, Chirigos MA. Immunomodulatory effects in mice of polyinosinic-polycytidylic acid complexed with poly-L lysine and carboxymethylcellulose. Cancer Res 1985; 45: 1058–65.

    Google Scholar 

  165. Knauf MJ, Bell DP, Hirtzer P, Luo Z-P, Young JD, Katre NV. Relationship of effective molecular size to systemic clearance in rats of recombinant interleukin-2 chemically modified with water-soluble polymers. J Biological Chem 1988; 263: 15064–70.

    Google Scholar 

  166. Katre NV, Knauf MJ, Laird WJ. Chemical modification of recombinant interleukin 2 by polyethylene glycol increases its potency in the murine Meth A sarcoma model. Proc Natl Acad Sci 1987; 84: 1487–91.

    Google Scholar 

  167. Kuga T, Komatsu Y, Yamasaki M, Sekine S, Miyaji H, Nishi T, Sato M, Yokoo Y, Asano M, Okabe M, Morimoto M, Itoh S. Mutagenesis of human granulocyte colony stimulating factor Biochemical and Biophysical Res Comm 1989; 159: 103–11.

    Google Scholar 

  168. Capon DJ, Chamow SM, Mordenti J, Marsters SA, Gregory T, Mitsuya H, Byrn RA, Lucas C, Wurm FM, Groopman JE, Broder S, Smith DH. Designing CD4 immunoadhesions for AIDS therapy. Nature 1989; 337: 525–8.

    Google Scholar 

  169. Huang JJ, Newton RC, Horuk R, Matthew JB, Covington M, Pezzella K, Lin Y. Muteins of human interleukin-1 that show enhanced bioactivities. FEBS Lett 1987; 223: 294–8.

    Google Scholar 

  170. Rosenberg SA, Grimm E, McGrogan M, Doyle M, Kawasaki E, Koths K, Mark DF. Biological activity of recombinant human interleukin-2 produced inEschericia coli. Science 1984; 223: 1412–5.

    Google Scholar 

  171. Lu HS, Boone TC, Souza Lm, Lai P-H. Disulfide and secondary structures of recombinant human granulocyte colony stimulating factor. Archives of Biochemistry and Biophysics 1989; 268: 81–92.

    Google Scholar 

  172. Moonen P, Mermod J-J, Ernst JF, Hirschi M, DeLamerter JF. Increased biological activity of deglycosylated recombinant human granulocyte/macrophage colony stimulating factor produced by yeast or animal cells. Proc Natl Acad Sci 1987; 84: 4428–31.

    Google Scholar 

  173. Lewis UJ, Singh RN, Lewis LJ, Seavy BK Sinha YN. Glycosylated ovine prolactin. Proc Natl Acad Sci USA 1984; 81: 385–9.

    Google Scholar 

  174. Maeger A, Leist T. Antigenic characteristics of glycosylated natural and unglycosylated recombinant human gamma-interferon. J Interferon Res 1986; 6: 225–32.

    Google Scholar 

  175. Le J, Rubin BY, Kelker HC, Feit C, Nagler C, Vilcek J. Natural and recombinant Escherichia coli-derived interferon-q differ in their reactivity with monoclonal antibody. J Immunol 1984; 132: 1300–4.

    Google Scholar 

  176. Pankov Yu A, Butnev U Yu. Multiple forms of pituitary prolactin, a glycosylated form of porcine prolactin with enhanced biological activity. Int J Pept Protein Res 1986; 28: 113–23.

    Google Scholar 

  177. Kelker HC, Yip YK, Anderson P, Vilcek J. Effects of glycosidase treatment on the physicochemical properties and biological activity of human interferon-g. J Biol Chem 1983; 258: 8010–3.

    Google Scholar 

  178. Spivak JL, Hogans BB. The in vivo metabolism of recombinant human erythropoietin in the rat. Blood 1989; 73: 90–3.

    Google Scholar 

  179. Fukuda MN, Sasaki H, Lopez L, Fukuda M. Survival of recombinant erythropoietin in the circulation: the role of carbohydrates. Blood 1989; 73: 84–9.

    Google Scholar 

  180. Dube S, Fisher JW, Powell JS. Glycosylation at specific sites of erythropoietin is essential for biosynthesis, secretion, and biological function. J Biological Chem 1988; 263; 17516–21.

    Google Scholar 

  181. Lefkovitz, I. Self and non-self discrimination by “restriction proteases”. Proc Natl Acad Sci USA 1986; 83 3437–8.

    Google Scholar 

  182. McFarlane IG. Hepatic clearance of serum glycoproteins. Clin Sci 1983; 64: 127–35.

    Google Scholar 

  183. Dufau ML, Catt KJ, Tsuruhara T. Retention ofin vitro biological activities by desialylated human luteinizing hormone and chorionic gonadotropin. Biochem Biophys Res Commun 1971; 44: 1022–9.

    Google Scholar 

  184. Aizawa S and Tavassoli M. Molecular basis of the recognition of intravenously transplanted hemopoietic cells by bone marrow. Proc Natl Acad Sci USA 1988; 85: 3180–3.

    Google Scholar 

  185. Kataoka M and Tavassoli M. Identification of lectin-like substances recognizing galactosyl residues of glycocon jugates on the plasma membrane of marrow sinus endothelium. Blood 1985; 65: 1163–71.

    Google Scholar 

  186. Aizawa S and Tavassoli M. Interaction of murine granulocyte-macrophage progenitors and supporting stroma involves a recognition mechanism with galactosyl and mannosyl specificities. J Clinical Investigation 1987; 80: 1698–705.

    Google Scholar 

  187. Aizawa S and Tavassoli M.In vitro homing of hemopoietic stem cells is mediated by a recognition system with galactosyl and mannosyl specificities. Proc Natl Acad 1987; 84: 4485–9.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Talmadge, J.E. Development of immunotherapeutic strategies for the treatment of malignant neoplasms. Biotherapy 4, 215–236 (1992). https://doi.org/10.1007/BF02174208

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02174208

Key words

Navigation