Skip to main content
Log in

Immunomodulatory effects of systemic low-dose recombinant interleukin-2 and lymphokine-activated killer cells in humans

  • Original articles
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Summary

The adoptive immunotherapy of human cancer using lymphokine-activated killer (LAK) cells in combination with high-dose systemic recombinant interleukin-2 (rIL-2) has been associated with global changes in several hematological and immunological parameters while imposing profound toxicity on patients. We have evaluated an alternative LAK cell therapy utilizing low-dose systemic rIL-2 in 27 consecutive patients with metastatic cancer. We report that the administration of systemic low-dose rIL-2 is also characterized by significant changes in immunological and hematological parameters, which are qualitatively similar to those induced by high-dose rIL-2. Low-dose systemic rIL-2, given by i.v. bolus, is cleared to baseline levels within 240 min of administration. The induction of lymphocytosis and eosinophilia, which has characterized other protocols, is also a feature of this protocol. In addition, low-dose systemic rIL-2/LAK cell immunotherapy results in increased peripheral blood mononuclear cell (PBMC) expression of T-cell activation markers such as OKIa, OKT10 and IL-2 receptor. PBMC sampled approximately 100 h after the final infusion of LAK cells demonstrated a statistically significant increase in their ability to kill natural killer (NK)-sensitive and NK-resistent cell lines such as K562 and Daudi compared to baseline values (P <.05). These data suggest that rIL-2-based immunotherapy using low-dose rIL-2 is capable of inducing quantitative hematological and immunological changes while (in combination with LAK cells) retaining the ability to mediate tumor regressionin vivo.

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. Atkins MB, Gould JA, Allegretta M, Li JJ, Dempsey RA, Rudders RA, Parkinson DR, Reichlin S, Mier JW (1986) Phase I evaluation of recombinant interleukin-2 in patients with advanced malignant disease. J Clin Oncol 4: 1380

    Google Scholar 

  2. Boldt DH, Mills BJ, Gemlo BT, Holden H, Mier J, Paietta E, McMannis JD, Escobedo LV, Sniecinski I, Rayner AA, Hawkins MJ, Atkins MB, Ciobanu N, Ellis TM (1987) Laboratory correlates of adoptive immunotherapy with recombinant interleukin-2 and lymphokine-activated killer cells in humans. Cancer Res 48: 4409

    Google Scholar 

  3. Cheever MA, Greenberg PD, Fefer A (1980) Specificity of adoptive chemoimmunotherapy of established syngeneic tumors. J Immunol 125: 711

    Google Scholar 

  4. Domzig W, Stadler BM, Herberman RB (1983) Interleukin-2 dependence of human natural (NK) killer cell activity. J Immunol 130: 1970

    Google Scholar 

  5. Eberlein TJ, Rosenstein M, Rosenberg SA (1982) Regression of a disseminated syngeneic solid tumor by systemic transfer of lymphoid cells expanded in interleukin-2. J Exp Med 156: 385

    Google Scholar 

  6. Eberlein TJ, Schoof DD, Jung S-E, Davidson DL, Gramolini B, McGrath K, Massaro AF, Wilson RE (1988) A new regimen of interleukin-2 and lymphokine-activated killer cells: efficacy without significant toxicity. Arch Intern Med 148: 2571

    Google Scholar 

  7. Eberlein TJ, Schoof DD, Michie HR, Massaro AF, Burger U, Wilmore DW, Wilson RE (1988) Ibuprofen causes reduced toxicity of IL-2 administration in patients with metastatic cancer. Arch Surg 124: 542

    Google Scholar 

  8. Emmrich F, Moll H, Simon MM (1985) Recombinant human interleukin-2 acts as a B-cell growth and differentiation promoting factor. Immunobiology 169: 97

    Google Scholar 

  9. Fernandez-Cruz E, Halliburton B, Feldman JD (1979) In vivo elimination by specific effector cells of an established syngeneic rat Moloney virus-induced sarcoma. J Immunol 123: 1772

    Google Scholar 

  10. Gillis S, Smith KA (1977) Long-term culture of tumor-specific cytotoxic T-cells. Nature 268: 154

    Google Scholar 

  11. Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA (1982) The lymphokine-activated killer cell phenomenon: lysis of NK resistant fresh solid tumor cells by IL-2 activated autologous human peripheral blood lymphocytes. J Exp Med 55: 1823

    Google Scholar 

  12. Krigel RL, Padavic-Shaller KA, Rudolph AR, Litwin S, Konrad M, Bradley EC, Comis RL (1988) A phase I study of recombinant interleukin 2 plus recombinant beta-interferon. Cancer Res 48: 3875

    Google Scholar 

  13. Lotze MT, Custer MC, Rosenberg SA (1986) Intraperitoneal administration of interleukin-2 in patients with cancer. Arch Surg 121: 1373

    Google Scholar 

  14. Morgan DA, Ruscetti FW, Gallo RC (1976) Selective in vitro growth of T-lymphocytes from normal human bone marrows. Science 193: 1007

    Google Scholar 

  15. Rosenberg SA (1985) Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313: 1485

    Google Scholar 

  16. Rosenberg SA (1987) 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 316: 889

    Google Scholar 

  17. Rosenberg SA, Grimm E, McGrogan M, Doyle M, Kawasaki E, Koths K, Mark DF (1984) Biological activity of recombinant human interleukin-2 produced inEscherichia coli. Science 223: 1412

    Google Scholar 

  18. Schoof DD, Gramolini B, Davidson D, Massaro A, Wilson RE, Eberlein TJ (1988) Adoptive immunotherapy of human cancer using low-dose recombinant interleukin-2 and lymphokine-activated killer cells. Cancer Res 48: 5007

    Google Scholar 

  19. Silberstein DS, Schoof DD, Rodrick ML, Gramolini BA, Tai P, Spry CJ, David JR, Eberlein TJ (1989) Characteristics of eosinophils in cancer patients treated with interleukin-2 generated LAK cells. J Immunol (in press)

  20. Taniguchi R, Matsui H, Fujita T, Takaoka C, Kashima N, Yoshimoto R, Hamuor J (1983) Structure and expression of a cloned cDNA for human interleukin-2. Nature 302: 305

    Google Scholar 

  21. Watson J (1979) Continuous proliferation of murine antigenspecific helper T-lymphocytes in culture. J Exp Med 150: 1510

    Google Scholar 

  22. West WH (1987) Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med 316: 898

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Additional information

Dr. Eberlein was a recipient of an American Cancer Society Career Development Award. This work is supported in part by NIH Grant CA-40555 and the Clinical Research Center Grant 20-9299

Rights and permissions

Reprints and permissions

About this article

Cite this article

Eberlein, T.J., Rodrick, M.L., Massaro, A.F. et al. Immunomodulatory effects of systemic low-dose recombinant interleukin-2 and lymphokine-activated killer cells in humans. Cancer Immunol Immunother 30, 145–150 (1989). https://doi.org/10.1007/BF01669422

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01669422

Keywords

Navigation