High Dose Interleukin-2 Therapy

  • Christian A. Petrulio
  • Gail DeRaffele
  • Howard L. Kaufman


Immunotherapy Interleukin-2 Melanoma Renal Cell Carcinoma Treatment 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Jemal, A., Murray, T., Ward, E., Samuels, A., Tiwari, R.C., Ghafoor, A., Feuer, E.J. and Thun, M.J: Cancer statistics CA Cancer J Clin 55:10–30, 2005.PubMedCrossRefGoogle Scholar
  2. 2.
    Nelson, BH: Regulatory T-cells and Tolerance. J. Immunol. 172:3983–3988, 2004.PubMedGoogle Scholar
  3. 3.
    Gaffen, S.L.: Signaling domains of the interleukin 2 receptor. Cytokine 14:63–77, 2001.PubMedCrossRefGoogle Scholar
  4. 4.
    He, Y.W. and Malek T.R: The structure and function of γc-dependent cytokines and receptors: regulation of T lymphocytes development and homeostasis. Crit. Rev. Immunol 18, 503–524, 1998.PubMedGoogle Scholar
  5. 5.
    Parrish-Novak, J., Foster, D.C., Holly, R.D. and Clegg, C.H: Interleukin-21 and the IL-21 receptor; novel effectors of NK and T cell responses. J. Leukoc. Biol 72, 856–863, 2002.PubMedGoogle Scholar
  6. 6.
    Rosenberg, S., Lotze, M., Muul, L., Leitman, S., Chang, A., Ettinghausen, S., Matory, Y., Skibber, J., Shiloni, E., Vetto, J., et al: Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Eng J Med 313:1485–1492, 1985.CrossRefGoogle Scholar
  7. 7.
    Lotze, M., Chang, A., Seipp, C., Simpson, C., Vetto, J., and Rosenberg, S: High-dose recombinant interleukin-2 in the treatment of patients with disseminated cancer. JAMA 256:3117–3124, 1986.PubMedCrossRefGoogle Scholar
  8. 8.
    Sadlack, B. et al: Ulcerative colitis-like disease in mice with a disrupted interleukin-gene. Cell 75, 253–261 1993.PubMedCrossRefGoogle Scholar
  9. 9.
    Sadlack, B. et al: Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur. J. Immunol 25, 3053–3059,1995.PubMedCrossRefGoogle Scholar
  10. 10.
    Sadlack, B., Kuhn, R., Schorle, H., Muller, W. & Horak, I: Development and proliferation of lymphocytes in mice deficient for both interleukins-2 and -4. Eur. J. Immunol. 24, 281–284, 1994.PubMedCrossRefGoogle Scholar
  11. 11.
    Malek, T. R., Yu, A., Vincek, V., Scibelli, P. & Kong, L: CD4 regulatory T cells prevent lethal autoimmunity in IL-2R-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17, 167–178, 2002.PubMedCrossRefGoogle Scholar
  12. 12.
    Malek, T. R., Porter, B. O., Codias, E. K., Scibelli, P. & Yu, A: Normal lymphoid homeostasis and lack of lethal autoimmunity in mice containing mature T cells with severely impaired IL-2 receptors. J. Immunol 164, 2905–2914, 2004.Google Scholar
  13. 13.
    Malek TR, Bayer AL. Tolerance, not immunity, crucially depends on IL-2. Nature Rev Immunol 4:665–674, 2004.CrossRefGoogle Scholar
  14. 14.
    Depper, J. M., Leonard, W. J., Robb, R. J., Waldmann, T. A. & Greene, W. C: Blockade of the interleukin-2 receptor by anti-Tac antibody: inhibition of human lymphocyte activation. J. Immunol 131, 690–696, 1983.PubMedGoogle Scholar
  15. 15.
    Gillis, S., Gillis, A. E. & Henney, C. S: Monoclonal antibody directed against interleukin 2 : Inhibition of T lymphocyte mitogenesis and the in vitro differentiation of alloreactive cytolytic T cells. J. Exp. Med. 154, 983–988, 1981.PubMedCrossRefGoogle Scholar
  16. 16.
    Van Parijs, L. et al: Functional responses and apoptosis of CD25 (IL-2Rα)-deficient T cells expressing a transgenic antigen receptor. J. Immunol. 158, 3738–3745,1997.PubMedGoogle Scholar
  17. 17.
    Kundig, T. M. et al. Immune responses in interleukin-2-deficient mice. Science 262, 1059–1061, 1993.PubMedCrossRefGoogle Scholar
  18. 18.
    D’Souza, W. N. & Lefrancois, L: IL-2 is not required for the initiation of CD8 T cell cycling but sustains expansion. J. Immunol 171, 5727–5735, 2003.PubMedGoogle Scholar
  19. 19.
    Leung, D. T., Morefield, S. & Willerford, D. M: Regulation of lymphoid homeostasis by IL-2 receptor signals in vivo. J. Immunol 164, 3527–3534, 2000.PubMedGoogle Scholar
  20. 20.
    Lotze, M., Grimm, E., Mazumder, A., Strausser, J., and Rosenberg, S: In vitro growth of cytotoxic human lymphocytes. Lysis of fresh and cultured autologous tumor by lymphocytes cultured in T cell growth factor (TCGF). Cancer Res 41:4420, 1981.PubMedGoogle Scholar
  21. 21.
    Mazumder, A., and Rosenberg, S: Successful immunotherapy of natural killer-resistant established pulmonary metastases by the intravenous adoptive transfer of syngeneic lymphocytes activated in vitro by interleukin-2. J Exp Med 159:495, 1984.PubMedCrossRefGoogle Scholar
  22. 22.
    Rosenberg, S., Mule, J., Spiess, P., Reichert, C., and Schwarz, S: Regression of Established Pulmonary Metastases and Subcutaneous Tumor Mediated by the Systemic Administration of High-Dose Recombinant Interleukin 2. J Exp Med 161:1169–1188, 1985.PubMedCrossRefGoogle Scholar
  23. 23.
    Rosenberg, S., Lotze, M., Muul, L., Leitman, S., Chang, A., Ettinghausen, S., Matory, Y., Skibber, J., Shiloni, E., Vetto, J., et al: Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Eng J Med 313:1485–1492.Google Scholar
  24. 24.
    Lotze, M., Chang, A., Seipp, C., Simpson, C., Vetto, J., and Rosenberg, S. 1986. High-dose recombinant interleukin-2 in the treatment of patients with disseminated cancer. JAMA 256:117–3124, 1985.CrossRefGoogle Scholar
  25. 25.
    Rosenberg, S., Lotze, M., Muul, L., Chang, A., Avis, F., Leitman, S., Linehan, W., Robertson, C., Lee, R., Rubin, J., 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 Eng J Med 316:889–897, 1987.CrossRefGoogle Scholar
  26. 26.
    Atkins, M., Lotze, M., Dutcher, J., Fisher, R., Weiss, G., Margolin, K., Abrams, J., Sznol, M., Parkinson, D., Hawkins, M., et al: High-dose recombinant interleukin-2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17:2105–2116, 1999.PubMedGoogle Scholar
  27. 27.
    Rosenberg, S., Yang, J., White, D., and Steinberg, S: Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann Surg. 228:307–319, 1998.PubMedCrossRefGoogle Scholar
  28. 28.
    Sparano, J., Fisher, R., Sunderland, M., Margolin, K., Ernest, M., Sznol, M., Atkins, M., Dutcher, J., Micetich, K., Weiss, G., 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 11:1969–1977, 1993.PubMedGoogle Scholar
  29. 29.
    Eton, O., Legha, S., Bedikian, A., Lee, J., Buzaid, A., Hodges, C., Ring, S., Papadopoulos, N., Plager, C., East, M., et al: Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol 20:2045–2052, 2002.PubMedCrossRefGoogle Scholar
  30. 30.
    Keilholz, U., Goey, S., Punt, C., Proebstle, T., Salzmann, R., Scheibenbogen, C., Schadendorf, D., Liendard, D., Enk, A., Dummer, R., et al: Interferon-alfa-2a and interleukin-2 with or without cisplatin in metastatic melanoma: a randomized trial of the European Organization for the Research and Treatment of Cancer Melanoma Cooperative Group. J Clin Oncol 15:2579–2588, 1997.PubMedGoogle Scholar
  31. 31.
    Rosenberg, S., Yang, J., Schwartzentruber, D., Hwu, P., Marincola, F., Topalian, S., Seipp, C., Einhorn, J., White, D., and Steinberg, S: Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone, or in combination with interleukin-2 and interferon-alfa-2b. J Clin Oncol 17:968–975, 1999.PubMedGoogle Scholar
  32. 32.
    Keilholz, U., Punt, C., Gore, M., Suciu, S., Kruit, W., Patel, P., Lienard, D., Thomas, J., Lehmann, F., and Eggermont, A: Dacarbazine, cisplatin and IFN-a2b with or without IL-2 in advanced melanoma: Final analysis of EORTC randomized phase III trial 18951. In ASCO. Chicago. 708 (abst 2848), 2003.Google Scholar
  33. 33.
    Atkins, M., Lee, S., Flaherty, L., Sosman, J., Sondak, V., and Kirkwood, J: A prospective randomized phase III trial of concurrent biochemotherapy (BCT) with cisplatin, vinblastine, dacarbazine (CVD), IL-2 and interferon alpha-2b (IFN) versus CVD alone in patients with metastatic melanoma (E3695): An ECOG-coordinated intergroup trial. In ASCO. Chicago. 708 (abstr 2847), 2003.Google Scholar
  34. 34.
    Fisher, R.I., Coltman, C.A., Jr., Doroshow, J.H., Rayner, A.A., Hawkins, M.J., Mier, J.W., Wiernik, P., McMannis, J.D., Weiss, G.R., Margolin, K.A., et al: Metastatic renal cancer treated with interleukin-2 and lymphokine-activated killer cells. A phase II clinical trial. Ann Intern Med 108:518–523, 1988.PubMedGoogle Scholar
  35. 35.
    Fyfe, G., Fisher, R.I., Rosenberg, S.A., Sznol, M., Parkinson, D.R., and Louie, A.C: Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 13:688–696, 1995.PubMedGoogle Scholar
  36. 36.
    Fisher, R.I., Rosenberg, S.A., and Fyfe, G: Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 6 Suppl 1:S55–57, 2000.PubMedGoogle Scholar
  37. 37.
    Bukowski, R.M: Natural history and therapy of metastatic renal cell carcinoma: the role of interleukin-2. Cancer 80:1198–1220, 1997.PubMedCrossRefGoogle Scholar
  38. 38.
    Yang, JC, Sherry, RM, Steinberg, SM, Topalian, SL, Schwartzentruber, DJ, Hwu, P, Seipp, CA, Rogers-Freezer, L, Morton, KE, White, DE, Liewehr, DJ, Merino, MJ, Rosenberg, SA: Randomized Study of High-Dose and Low Dose Interleukin-2 in patients with Metastatic Renal Cancer. J Clin Oncol Aug 15;21 (16):3127–32, 2003.CrossRefGoogle Scholar
  39. 39.
    Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V, McGrath PC, Caton JR Jr, Munshi N, Crawford ED: Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer N Eng J Med 345(23): 1655–59, 2001.CrossRefGoogle Scholar
  40. 40.
    Pantuck AJ, Belldegrun AS, Figlin RA: Nephrectomy and interleukin-2 for metastatic renal-cell carcinoma. N Engl J Med 345(23) 1711–1712, 2001.PubMedCrossRefGoogle Scholar
  41. 41.
    Marincola, F., Venzon, D., White, D., Rubin, J., Lotze, M., Simonis, T., Balkissoon, J., Rosenberg, S., and Parkinson, D: HLA association with response and toxicity in melanoma patients treated with interleukin 2-based immunotherapy. Cancer Res 52:6561–6566, 1992.PubMedGoogle Scholar
  42. 42.
    Rubin, J., Elwood, L., Rosenberg, S., and Lotze, M: Immunohistochemical correlates of response to recombinant interleukin-2-based immunotherapy in humans. Cancer Res 49:7086–7092, 1986.Google Scholar
  43. 43.
    Horikoshi, T., Ito, S., Wakamatsu, K., Onodera, H., and Eguchi, H: Evaluation of melanin-related metabolites as markers of melanoma progression. Cancer 73:629–636, 1994.PubMedCrossRefGoogle Scholar
  44. 44.
    Phan, G., Attia, P., Steinberg, S., White, D., and Rosenberg, S: Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin Oncol. 19:3477–3482, 2001.PubMedGoogle Scholar
  45. 45.
    Jonasch E, George D, Atkins MB: Renal neoplasia. In: Brenner B, ed. Brenner & Rector’s The Kidney, 7th ed. Philadelphia: Saunders; 1895–1923, 2004.Google Scholar
  46. 46.
    Royal RE, Steinberg SM, Krouse RS, et al: Correlates of response to IL-2 therapy in patients treated for metastatic renal cancer and melanoma. Cancer J Sci Am 2:91, 1996.PubMedGoogle Scholar
  47. 47.
    Upton MP, Parker RA, Youmans A, McDermott DF, Atkins MB: Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy. J Immunol 28: 488–95, 2005.Google Scholar
  48. 48.
    Said J: Biomarker discover in urogenital cancer. Biomarkers Nov;10 Suppl 1:S83–6, 2005.CrossRefGoogle Scholar
  49. 49.
    Bui MH, Seligson D, Han KR, et al: Carbonic anhydrase IX is an independent predictor of survival in advanced renal cell carcinoma: implications for pronosis and therapy. Clin Cancer Res 9:802–811, 2003.PubMedGoogle Scholar
  50. 50.
    Mukouyama H, Janzen NK, Hernandez JM, et al: Generation of kidney cancer-specific antitumor immune responses using peripheral blood moncytes transduced with a recombinant adenovirus encoding carbonic anhydrase 9. Clin Cancer Res 10:1421–1429, 2004.PubMedCrossRefGoogle Scholar
  51. 51.
    Schwartzentruber, D: Guidelines for the Safe Administration of High-Dose Interleukin-2. J Immunother 24:287–293, 2001.PubMedCrossRefGoogle Scholar
  52. 52.
    Guirguis, LM, Yang, JC, White, DE, Steinberg SM, Liewehr, DJ, Rosenberg ,SA, Schwartzentruber, DJ: Safety and efficacy of high-dose Interleukin-2 therapy in patients with brain metastases. J Immunother Jan-Feb; 25(1):82–7, 2002.CrossRefGoogle Scholar
  53. 53.
    Mier, J., Vachino, G., Klempner, M., Aaronson, F., Noring, R., Smith, S., Brandon, E., Laird, W., and Atkins, M: Inhibition of interleukin-2-induced tumor necrosis factor release by dexamethasone: prevention of an acquired neutrophil chemotaxis defect and differential suppression of interleukin-2-associated side effects. Blood 76:1933–1940, 1990.PubMedGoogle Scholar
  54. 54.
    Du Bois, J., Trehu, E., Mier, J., Shapiro, L., Epstein, M., Klempner, M., Dinarello, C., Kappler, K., Ronayne, L., Rand, W., et al: Randomized placebo-controlled clinical trial of high-dose interleukin-2 in combination with a soluble p75 tumor necrosis factor receptor immunoglobulin G chimera in patients with advanced melanoma and renal cell carcinoma. J Clin Oncol 15:1052–1062,1997.PubMedGoogle Scholar
  55. 55.
    Kilbourn, R., Fonseca, G., Trissel, L., and Griffith, O: Strategies to reduce side effects of interleukin-2: evaluation of the antihypotensive agent NG-monomethyl-L-arginine. Cancer J Sci Am 6:S21–30, 2000.PubMedGoogle Scholar
  56. 56.
    Samlowski, W., Petersen, R., Cuzzocrea, S., Macarthur, H., Burton, D., McGregor, J., and Salvemimi, D: A nonpeptidyl mimic of superoxide dismutase, M40403, inhibits dose-limiting hypotension associated with interleukin-2 and increases its antitumor effects. Nat Med 9:750–755, 2003.PubMedCrossRefGoogle Scholar
  57. 57.
    Dillman, R., O’Connor, A., Simpson, L., Barth, N., VanderMolen, L., and Vanderplas, P: Does Continuous-Infusion Interleukin-2 Increase Survival in Metastatic Melanoma? Am J Clin Oncol 26:141–145, 2003.PubMedCrossRefGoogle Scholar
  58. 58.
    Thompson, J., Lee, D., Lindgren, C., Benz, L., Collins, C., Levitt, D., and Fefer, A: Influence of dose and duration of infusion of interleukin-2 on toxicity and immunomodulation. J Clin Oncol 6:669–678, 1988.PubMedGoogle Scholar
  59. 59.
    Liu, K., and Rosenberg, S: Interleukin-2-independent proliferation of human melanoma-reactive T lymphocytes transduced with an exogenous IL-2 gene is stimulation dependent. J Immunother 26:190–201, 2003.PubMedCrossRefGoogle Scholar
  60. 60.
    Radny, P., Caroli, U., Bauer, J., Paul, T., Schlegel, C., Eigentler, T., Weide, B., Schwarz, M., and Garbe, C: Phase II trial of intralesional therapy with interleukin-2 in soft-tissue melanoma metastases. Br J Cancer 89:1620–1626, 2003.PubMedCrossRefGoogle Scholar
  61. 61.
    Mahnke, K., Qian, Y., Knop, J., and Enk, A: Induction of CD4+/CD25+ regulatory T cells by targeting of antigens to immature dendritic cells. Blood 101:4862–4869, 2003.PubMedCrossRefGoogle Scholar
  62. 62.
    Shimizu, J., Yamazaki, S., and Sakaguchi, S: Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol. 163:5211–5218, 1999.PubMedGoogle Scholar

Copyright information

© Springer 2007

Authors and Affiliations

  • Christian A. Petrulio
    • 1
  • Gail DeRaffele
    • 1
  • Howard L. Kaufman
    • 1
  1. 1.The Tumor Immunology Laboratory, Division of Surgical OncologyColumbia UniversityNew YorkUSA

Personalised recommendations