Clinical Immunotherapeutics

, Volume 1, Issue 4, pp 271–281 | Cite as

Interleukins in Cancer Therapy

Rationale and Current Status
  • Leslie Oleksowicz
  • Joseph Sparano
  • Kevin O’Boyle
  • Usha Venkatraj
  • Peter H. Wiernik
  • Janice P. Dutcher
Review Article Disease Treatment Review


The interleukins function as intercellular hormones, and have the capacity to alter the activity of a target cell population. Immunotherapy with interleukin-2 (IL-2) constitutes a new treatment strategy for malignancies otherwise not responsive to traditional cytotoxic chemotherapy.

In advanced renal cell carcinoma, studies using high dose bolus IL-2 alone have resulted in mean objective response rates of approximately 15% (0 to 27%). Durable responses in some patients have translated into increased survival. With advanced melanoma, high dose bolus IL-2 therapy alone produces response rates ranging from 21 to 24%, although other studies using lower doses, different drug preparations or different schedules have resulted in lower response rates. Studies are now under way using IL-2 in combination with interferons, cytotoxic chemotherapy, monoclonal antibodies and tumour infiltrating lymphocytes in an attempt to enhance the biological activity of IL-2.

Another promising use of IL-2 therapy is in the treatment of acute leukaemia. Several small studies have shown benefit of IL-2 given to patients in early relapse, leading to normalisation of bone marrow and prolonged remissions in some patients. IL-2 is currently being investigated as a post-transplant adjuvant strategy in patients undergoing bone marrow transplantation for haematological malignancies.

Newly characterised interleukins such as IL-4 and IL-6 have demonstrated preclinical antitumour and immunoenhancing properties, resulting in their recent introduction into clinical trials. Additionally, IL-6 has demonstrated thrombopoietic enhancing activity in early clinical trials and has a potential application in ameliorating thrombocytopenia associated with myeloablative chemotherapy.

In summary, these interleukins have proven to be effective additions to treatment strategies in oncology.


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  1. 1.
    Mule JJ, Shu S, Schwartz SL, et al. Adoptive immunotherapy of established pulmonary metastases with LAK cells and recombinant interleukin-2. Science 1984; 225: 1487–9PubMedCrossRefGoogle Scholar
  2. 2.
    Whittington R, Faulds D. Interleukin-2: a review of its pharmacological properties and therapeutic use in patients with cancer. Drugs 1993; 46: 446–514PubMedCrossRefGoogle Scholar
  3. 3.
    Rosenberg SA, Lotze MT, Muul LM, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 1985; 313: 1485–92PubMedCrossRefGoogle Scholar
  4. 4.
    Rosenberg SA, Lotze MT, Muul LM, et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 1987; 316: 889–97PubMedCrossRefGoogle Scholar
  5. 5.
    Fisher RI, Coltman CA, Doroshow JH, et al. Metastatic renal cancer treated with interleukin-2 and lymphokine-activated killer cells. Ann Int Med 1988; 108: 518–23PubMedGoogle Scholar
  6. 6.
    Rosenberg SA. The immunotherapy and gene therapy of cancer. J Clin Oncol 1992; 10: 180–99PubMedGoogle Scholar
  7. 7.
    Abrams S, Rayner AA, Wiernik PH, et al. High-dose recombinant interleukin-2 alone: a regime with limited activity in the treatment of advanced renal cell carcinoma. J Natl Cancer Inst 1990; 82: 1202–6PubMedCrossRefGoogle Scholar
  8. 8.
    Atkins M, Sparano J, Fisher RI, et al. Randomized phase II trial of high dose IL-2 alone or in combination with interferon α-2B in advanced renal cell carcinoma. J Clin Oncol 1993; 11: 661–70PubMedGoogle Scholar
  9. 9.
    Poo WJ, Fynan T, Davis C, et al. High dose recombinant interleukin-2 alone in patients with metastatic renal cell carcinoma. Proc Am Soc Clin Oncol 1991; 10: 173Google Scholar
  10. 10.
    Negrier S, Philip T, Stoter G, et al. Interleukin-2 with or without LAK cells in metastatic renal cell carcinoma: a report of a European multicentre study. Eur J Cancer Clin Oncol 1989; 25 (Suppl 3): s21–s28PubMedGoogle Scholar
  11. 11.
    Geertsen PF, Hermann GG, von der Maase H, et al. Treatment of metastatic renal cell carcinoma by continuous intravenous infusion of recombinant interleukin-2: a single-center phase II study. J Clin Oncol 1992; 10: 753–9PubMedGoogle Scholar
  12. 12.
    Bukowski RM, Goodman P, Crawford ED, et al. Phase II trial of high dose intermittant interleukin-2 in metastatic renal cell carcinoma: a Soutwest Oncology Group Study. J Natl Cancer Inst 1990; 82: 142–6CrossRefGoogle Scholar
  13. 13.
    Sleijfer D, Jannsen R, Willemse P, et al. Subcutaneous (s.c.) interleukin 2 (IL-2) (Cetus) in patients with metastatic renal cell cancer (RCC). Proc Am Soc Clin Oncol 1991; 10: 163Google Scholar
  14. 14.
    Brunda MJ, Bellantini D, Sulich V. In vivo antitumor activity of combinations of interferon-α and interleukin-2 in a murine model. Correlation of efficacy with the induction of cytotoxic cells resembling natural killer cells. Int J Cancer 1987; 40: 365–71PubMedCrossRefGoogle Scholar
  15. 15.
    Iigo M, Sakurai J, Tamura T, et al. In vivo antitumor activity of multiple injections of recombinant interleukin-2, alone and in combination with three different types of recombinant interferon, on various syngeneic murine tumors. Cancer Res 1988; 48: 5810–7Google Scholar
  16. 16.
    Figlin RA, Belldegrun A, Moldawer N, et al. Concomitant administration of recombinant human interleukin-2 and recombinant interferon alpha-2A: an active outpatient regimen in metastatic renal cell carcinoma. J Clin Oncol 1992; 10: 414–21PubMedGoogle Scholar
  17. 17.
    Bergmann L, Fenchel K, Weidmann E, et al. Daily alternating administration of high-dose alpha-2b-interferon and interleukin-2 bolus infusion in metastatic renal cell cancer. Cancer 1993; 72: 1733–42PubMedCrossRefGoogle Scholar
  18. 18.
    Mittleman A, Puccio C, Ahmed T, et al. A phase II trial of interleukin-2 by continuous infusion and interferon by intramuscular injection in patients with renal cell carcinoma. Cancer 1991; 68: 1699–702CrossRefGoogle Scholar
  19. 19.
    Lipton A, Harvey H, Givant E, et al. Interleukin-2 (IL-2) and interferon alpha-2a (INFα) outpatient therapy for metastatic renal cell carcinoma. J Immunother 1993; 13: 122–9CrossRefGoogle Scholar
  20. 20.
    Atzpodien J, Korfer A, Menzel T, et al. Home therapy using recombinant human IL-2 and IFN-α2b in patients with metastatic renal cell carcinoma. Proc Am Soc Clin Oncol 1991; 10: 177Google Scholar
  21. 21.
    Dutcher JP, Fisher RI, Weiss G, et al. An outpatient (OPT) regimen of subcutaneous (SC) interleukin-2 (IL-2) plus alpha-interferon (IFN) in metastatic renal cell cancer (RCC). Proc Am Soc Clin Oncology 1993; 12: 248Google Scholar
  22. 22.
    Rosenberg SA, Lotze MT, Yang J, et al. Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg 1989; 210: 474–85PubMedCrossRefGoogle Scholar
  23. 23.
    Dutcher JP, Creekmore S, Weiss GR, et al. Phase II study of high dose interleukin-2 and lymphokine activated killer cells in patients with metastatic malignant melanoma. J Clin Oncol 1989; 7: 477–85PubMedGoogle Scholar
  24. 24.
    Bar HM, Sznol M, Atkins MB, et al. Metastatic malignant melanoma treated with combined bolus and continuous infusion interleukin-2 and lymphokine-activated killer cells. J Clin Oncol 1990; 8: 1138–47PubMedGoogle Scholar
  25. 25.
    West WH, Tauer KW, Yanelli JR, et al. Constant-infusion IL-2 recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med 1987; 316: 898–905PubMedCrossRefGoogle Scholar
  26. 26.
    Gaynor ER, Weiss GR, Margolin KA, et al. Phase I study of high-dose continuous-infusion recombinant interleukin-2 and autologous lymphokine-activated killer cells in patients with metastatic or unresectable malignant melanoma and renal cell carcinoma. J Natl Cancer Inst 1990; 82: 1397–402PubMedCrossRefGoogle Scholar
  27. 27.
    Dutcher JP, Gaynor ER, Boldt DH, et al. A phase II study of high dose continuous infusion interleukin-2 with lymphokine activated killer cells. J Clin Oncol 1991; 9: 641–8PubMedGoogle Scholar
  28. 28.
    Parkinson DR, Abrams JS, Wiernik PH, et al. Interleukin-2 therapy in patients with metastatic malignant melanoma: a phase II study. J Clin Oncol 1990; 8: 1650–6PubMedGoogle Scholar
  29. 29.
    Rosenberg SA, Lotze MT, Yang JC, et al. Prospective, randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. J Natl Cancer Inst 1993; 85: 622–31PubMedCrossRefGoogle Scholar
  30. 30.
    Richards JM, Bajorin DF, Vogelzang NJ, et al. Treatment of metastatic melanoma with continuous intravenous IL-2 + LAK cells: a randomized trial. Proc Am Soc Clin Oncol 1990; 9: 279Google Scholar
  31. 31.
    McCabe MS, Stablein D, Hawkins MJ. The modified group C experience — phase III randomized trials of IL-2 vs IL-2/LAK in advanced renal cell carcinoma and advanced melanoma. Proc Am Soc Clin Oncol 1991; 10: 213Google Scholar
  32. 32.
    Mitchell MS, Kempf RA, Harel W, et al. Effectiveness and tolerability of low-dose cyclophosphamide and low-dose intravenous interleukin-2 in disseminated melanoma. J Clin Oncol 1988; 6: 409–24PubMedGoogle Scholar
  33. 33.
    Berd D, Maguire HC Jr, Mastrangelo MJ. Potentiation of human cell-mediated and humoral immunity by low-dose cyclophosphamide. Cancer Res 1984; 44: 1275–80PubMedGoogle Scholar
  34. 34.
    Lindemann A, Hoffken K, Schmid RE, et al. A phase II study of low dose cyclophosphamide and recombinant interleukin-2 in metastatic renal cell carcinoma and malignant melanoma. Cancer Immunol Immunother 1989; 28: 275–81PubMedCrossRefGoogle Scholar
  35. 35.
    Whitehead RP, Kopecky KJ, Samson KM, et al. Aphase II study of IV bolus recombinant interleukin 2 in metastatic malignant melanoma: a Southwest Oncology Group study. Proc Am Soc Clin Oncol 1989; 8: 284Google Scholar
  36. 36.
    Perez EA, Scudder SA, Meyers FA, et al. Weekly 24-hour continuous infusion interleukin-2 for metastatic melanoma and renal cell carcinoma: a phase I study. J Immunother 1991; 10: 57–62PubMedCrossRefGoogle Scholar
  37. 37.
    Badhan-Raj S, Cordon-Card C, Carswell E, et al. Phase I trial of a mouse monoclonal antibody against GD3 ganglioside in patients with melanoma: induction of inflammatory responses at tumor sites. J Clin Oncol 1988; 6: 1636–48Google Scholar
  38. 38.
    Bajorin D, Chapman P, Wong G, et al. Phase I evaluation of a combination of monoclonal antibody R24 and interleukin 2 in patients with metastatic melanoma. Cancer Res 1990; 50: 7490–5PubMedGoogle Scholar
  39. 39.
    Ellenhorn JDI, Hirsch R, Schreiber H, et al. In vivo administration of anti-CD3 prevents progressive tumor growth. Science 1988; 242: 569–71PubMedCrossRefGoogle Scholar
  40. 40.
    Sosman JA, Weiss GR, Margolin KA, et al. Phase IB clinical trial of anti-CD3 followed by high-dose bolus interleukin-2 in patients with metastatic melanoma and advanced renal cell carcinoma: clinical and immunologic effects. J Clin Oncol 1993; 11: 1496–505PubMedGoogle Scholar
  41. 41.
    Rhinehart JJ, Triozzi PL, Lee HM, et al. The effect of intensive chemotherapy and recombinant human IL-2 (rhIL-2) in a murine tumor model. Proc Am Assoc Cancer Res 1989; 31: 277Google Scholar
  42. 42.
    Demchak PA, Mier JW, Robert NJ, et al. Interleukin-2 and high-dose cisplatin in patients with metastatic melanoma: a pilot study. J Clin Oncol 1991; 9: 1821–30PubMedGoogle Scholar
  43. 43.
    Atkins MB, O’Boyle K, Sosman J, et al. A multi-institutional phase II trial of intensive combination chemoimmunotherapy for metastatic melanoma. Proc Am Soc Clin Oncol 1993; 12: 394Google Scholar
  44. 44.
    Guadagni F, Schlom J, Johnston WW, et al. Selective interferon-induced enhancement of tumor-associated antigens on a spectrum of freshly isolated human adenocarcinoma cells. J Natl Cancer Inst 1989; 81: 502–11PubMedCrossRefGoogle Scholar
  45. 45.
    Cameron RB, McIntosh JK, Rosenberg SA. Synergistic antitumor effects of combination immunotherapy with recombinant interleukin-2 and recombinant hybrid alpha-interferon in the treatment of established murine hepatic metastases. Cancer Res 1988; 48: 5810–7PubMedGoogle Scholar
  46. 46.
    Rosenberg SA, Lotze MT, Yang JC, et al. Combination therapy with interleukin-2 and alpha-interferon for the treatment of patients with advanced cancer. J Clin Oncol 1989; 7: 1863–74PubMedGoogle Scholar
  47. 47.
    Sparano JA, Fisher RI, Sunderland M, et al. Randomized phase III trial of treatment with high-dose interleukin-2 either alone or in combination with interferon alpha-2a in patients with advanced melanoma. J Clin Oncol 1993; 11: 1969–77PubMedGoogle Scholar
  48. 48.
    Lotzova E. The role of natural killer cells in immune surveillance against malignancies. Cancer Bull 1984; 36: 215–7Google Scholar
  49. 49.
    Archimbaud E, Bailly M, Dore JF. Inducibility of lymphokine activated killer (LAK) cells in patients with acute myelogenous leukaemia in complete remission and its clinical relevance. Br J Haematol 1991; 77: 328–34PubMedCrossRefGoogle Scholar
  50. 50.
    Lotzova E, McCredie KB, Muesse L, et al. Natural killer cells in man; their possible involvement in leukemia and bone marrow transplantation. In: Baum SJ, Ledney GD, editors. Experimental hematology today. New York: Springer-Verlag, 1979: 207–15Google Scholar
  51. 51.
    Lotzova E, Savary CA, Keating MJ. Studies on the mechanism of defective natural killing in leukemia-diseased patients. Exp Hematol 1982; 10: 83–9Google Scholar
  52. 52.
    Fujimiya Y, Pattengale PK. Characterization of NK cells in patients with chronic myelogenous leukemia. In: Herberman RB, Callewaert DM, editors. Mechanisms of cytotoxicity by NK cells. New York: Academic Press, 1985: 521–31Google Scholar
  53. 53.
    Foa R, Meloni G, Guarini A, et al. Has IL-2 a role in the management of minimal residual disease for acute leukemia? Leukemia 1992; 6 (Suppl. 4): 92–4PubMedGoogle Scholar
  54. 54.
    Foa R, Meloni G, Tosti S, et al. Treatment of acute myeloid leukemia patients with recombinant interleukin 2: a pilot study. Br J Haematol 1991; 77: 491–6PubMedCrossRefGoogle Scholar
  55. 55.
    Lim SH, Newland AC, Kelsey S, et al. Continuous intravenous infusion of high dose recombinant interleukin-2 for acute myeloid leukemia — a phase II study. Cancer Immunol Immunother 1992; 34: 337–42PubMedCrossRefGoogle Scholar
  56. 56.
    Maraninchi D, Blaise D, Viens P, et al. High dose recombinant interleukin-2 and acute myeloid leukemia in relapse. Blood 1991; 78: 2182–7PubMedGoogle Scholar
  57. 57.
    Heslop HE, Gottlieb DJ, Bianchi AC, et al. In vivo induction of gamma-interferon and tumour necrosis factor by interleukin-2 infusion following intensive chemotherapy or autologous bone marrow transplantation. Blood 1989; 74: 1374–80PubMedGoogle Scholar
  58. 58.
    Charak BS, Brynes RK, Groshen S, et al. Bone marrow transplantation with interleukin-2-activated bone marrow followed by interleukin-2 therapy for acute myeloid leukemia in mice. Blood 1990; 76: 2187–90PubMedGoogle Scholar
  59. 59.
    Higuchi CM, Thompson JA, Petersen FB, et al. Toxicity and immunomodulatory effects of interleukin-2 after autologous bone marrow transplantation for hematologic malignancies. Blood 1991; 77: 2561–8PubMedGoogle Scholar
  60. 60.
    Soifer RJ, Murray C, Cochran K, et al. Clinical and immunologic effects of prolonged infusion of low-dose recombinant interleukin-2 after autologous and T-cell-depleted allogeneic bone marrow transplantation. Blood 1992; 79: 517–26Google Scholar
  61. 61.
    Slavin S, Or R, Kapelushnik Y, et al. Immunotherapy of minimal residual disease in conjunction with autologous and allogenic bone marrow transplantation. Leukemia 1992; 6 (Suppl 4): 164–6PubMedGoogle Scholar
  62. 62.
    Benyunes M. York A, Lindren C, et al. IL-2 + LAK as consolidative therapy after autologous BMT for hematologic malignancies: a feasibility trial. Proc Am Soc Clin Oncol 1992; 11: 1082Google Scholar
  63. 63.
    Hamon MD, Prentice HG, Gottlieb DJ, et al. Immunotherapy with interleukin-2 after ABMT in AML. Bone Marrow Transplant 1993; 11: 399–401PubMedGoogle Scholar
  64. 64.
    Soiffer R, Murray C, Ritz J. Low dose interleukin-2 (IL-2) following bone marrow transplantation (BMT) for hematologic malignancy. Proc Am Soc Clin Oncol 1993; 12: 300Google Scholar
  65. 65.
    Oken MM, Kim K, Mazza JJ, et al. Maintenance low dose ARAC improves complete remission duration from salvage induction therapy for relapsed and refractory acute myeloid leukemia. Proc Am Soc Clin Oncol 1991; 10: 739Google Scholar
  66. 66.
    Dutcher P, Wiernik PH, Todd M, et al. Interleukin-2 as maintenance therapy of acute myelogenous leukemia in second remission. Proc Int Soc Exp Hematol 1993; 21: 142Google Scholar
  67. 67.
    Bergmann L, Jahan B, Heil G, et al. Interleukin-2 inverts remission duration in 2nd remission of AML: the antileukemic effect may be caused by specific CD4+ cytotoxic lymphocytes. Proc Am Assoc Cancer Res 1993; 34: 1182Google Scholar
  68. 68.
    Baumgarten E, Schmid H, Baurmann H, et al. Phase I/II trial with low dose interferon-gamma and interleukin-2 in children with high-risk malignancies after autologous bone marrow transplantation. Cytokines in Hemopoiesis, Oncology and AIDS; 1991 June 19–22; Hannover, Germany: 101Google Scholar
  69. 69.
    Mier JW, Aronson FR, Numerof RP, et al. Toxicity of immunotherapy with interleukin-2 and lymphokine-activated killer cells. Pathol Immunopathol Res 1988; 7: 459–76PubMedCrossRefGoogle Scholar
  70. 70.
    Widmer MB, Grabstein KH. Regulation of cytotoxic T-lymphocyte generation by B-cell stimulating factor. Nature 1987; 326: 795–8PubMedCrossRefGoogle Scholar
  71. 71.
    Trenn G, Takayamma H, Hu-Li J, et al. B cell stimulatory factor 1 (IL-4) enhances the development of cytotoxic T-cells from Lyt-2+ resting murine T-lymphocytes. J Immunol 1988; 140: 1101–6PubMedGoogle Scholar
  72. 72.
    Kinashi T, Inaba K, Tsubata T, et al. Differentiation of an interleukin-3 dependent precursor B-cell clone into immunoglobulin-producing cells in vitro. Proc Natl Acad Sci USA 1988; 85: 4473–7PubMedCrossRefGoogle Scholar
  73. 73.
    Taylor CW, Grogan TM, Salmon SE. Effects of IL-4 on the in vitro growth of human lymphoid and plasma cell neoplasms. Blood 1990; 75: 1114–8PubMedGoogle Scholar
  74. 74.
    Freimann J, Estrov Z, Itoh K, et al. Phase I studies of IL-4 in patients with hematologic malignancies. Blood 1990; 76 (Suppl. 1): 93Google Scholar
  75. 75.
    Maher D, Boyd A, McKendrick J, et al. Rapid response of B-cell malignancies induced by IL-4. Blood 1990; 76 (Suppl. 1): 152Google Scholar
  76. 76.
    Maher DW, Davis I, Boyd AW, et al. Human IL-4: an immunomodulator with potential therapeutic applications. Prog Growth Factor Res 1991; 3: 43–56PubMedCrossRefGoogle Scholar
  77. 77.
    Mule JJ, Custer MC, Travis WD, et al. Cellular mechanisms of the antitumor activity of recombinant IL-6 in mice. J Immunol 1992; 148: 2622–7PubMedGoogle Scholar
  78. 78.
    Mule JJ, Marcus JC, Yang JC, et al. Clinical application of IL-6 in cancer therapy. Res Immunol 1992; 143: 777–9PubMedCrossRefGoogle Scholar
  79. 79.
    Aronson FR, Sznol M, Mier JW, et al. Interleukin-6. Phase I trials of 1 and 120 hour intravenous infusions. Proc Am Soc Clin Oncol 1993; 12: 292Google Scholar
  80. 80.
    Chang A, Mitelman A, Boros L, et al. Phase I study of interleukin-6 (IL-6) in cancer patients treated with ifosfamide, carboplatin and etoposide (ICE). Blood 1992; 80 (Suppl. 1): 89Google Scholar

Copyright information

© Adis International Limited 1994

Authors and Affiliations

  • Leslie Oleksowicz
    • 1
  • Joseph Sparano
    • 1
  • Kevin O’Boyle
    • 1
  • Usha Venkatraj
    • 1
  • Peter H. Wiernik
    • 1
  • Janice P. Dutcher
    • 1
  1. 1.Department of OncologyThe Albert Einstein College of Medicine, Montefiore Medical Center HospitalBronxUSA

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