Skip to main content
Log in

Clinical trial of natural human lymphocyte-derived interleukin 2 in cancer patients: Effects on cytokine production and suppressor cell status

  • Published:
Biotherapy

Abstract

Lymphocyte-derived, natural, glycosylated interleukin 2 (IL 2) may have different effectsin vivo than the non-glycosylated recombinant IL 2 hitherto employed in clinical trials. To test this, 9 tumor patients were given 3–6 × 106 U/day natural IL 2 by continuous infusion for 5 days. Compared with previously published results obtained using recombinant IL 2, as far as similar tests were performed, no unexpected results were obtained with natural IL 2 in the present study. Plasma TNF-α levels increased considerably during therapy, IFN-γ very slightly, whereas IL 2-stimulated secretion of either cytokinein vitro fluctuated greatly. CD 16+ and CD25+ cells increased and CD45R+ cells decreased after treatment, consistent with significant lymphocyte activationin vivo. MHC-unrestricted cytotoxicity increased after treatment. The level of CD8+ cells was and remained within the normal range, although suppressive activity generated in mixed lymphocyte culture was deficient prior to therapy. Interestingly, this normalised after therapy. These results extend studies of immunological monitoring of patients receiving IL 2, based on the first trial using natural rather than recombinant IL 2.

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.

Similar content being viewed by others

Abbreviations

CTX:

cytotoxicity

LU:

lytic unit

MLC:

mixed lymphocyte culture

PBMC:

peripheral blood mononuclear cells

References

  1. Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, Matory YL et al. Observations on the systemic administration of autologous lymphokineactivated killer cells and recombinant interleukin 2 to patients with metastatic cancer. N Eng J Med 1985; 313: 1485–92.

    Google Scholar 

  2. Rosenberg SA, Lotze MT, Yang JC, Aebersold PM, Linehan WM, Seipp CA, White DE. Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg 1989; 210: 474–85.

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  4. Lotze MT, Frana LW, Sharrow SO, Robb RJ, Rosenberg SA.In vivo administration of purified human interleukin 2. I Half-life and immunologic effects of the Jurkat cell line-derived interleukin 2. J Immunol 1985; 134: 157–66.

    PubMed  Google Scholar 

  5. Frank MB, Watson J, Mochizuki D, Gillis S. Biochemical and biologic characterisation of lymphocyte regulatory molecules. VIII. Purification of interleukin 2 from a human T cell leukemia. J Immunol 1981; 127: 2361–5.

    PubMed  Google Scholar 

  6. Pawelec G, Schwulera U, Blaurock M, Busch FW, Rehbein A, Balko I, Wernet P. Relative cloning efficiencies and long-term propagation capacity for T cell clones of highly purified natural interleukin 2 compared to recombinant interleukin 2 in man. Immunobiology 1987; 174: 67–75.

    PubMed  Google Scholar 

  7. Pawelec G, Schwulra U, Lenz H, Owsianowski M, Bühring HJ, Schlag H, Schneider E, Schaudt K, Ehninger G. Lymphokine release, suppressor cell generation, cell surface markers, and cytotoxic activity in cancer patients receiving natural interleukin-2. Mol Biother 1990; 2: 44–9.

    PubMed  Google Scholar 

  8. Bindon C, Czerniecki M, Ruell P, Edwards A, McCarthy WH, Harris R, Hersey P. Clearance rates and systemic effects of intravenously administered interleukin 2 containing preparations in human subjects. Br J Cancer 1983; 47: 123–33.

    PubMed  Google Scholar 

  9. Ellis TM, Creekmore SP, McMannis JD, Braun DP, Harris JA, Fisher RI. Appearance and phenotypic characterization of circulating Len 19 ÷ cells in cancer patients receiving recombinant interleukin 2. Cancer Res 1988; 48: 6597–602.

    PubMed  Google Scholar 

  10. Lotze MT, Custer MC, Sharrow SO, Rubin LA, Nelson DL, Rosenberg SA.In vivo administration of purified interleukin 2 to patients with cancer: development of interleukin 2-receptor positive cells and circulating soluble interleukin 2-receptors following interleukin 2 administration. Cancer Res 1987; 47: 2188–95.

    PubMed  Google Scholar 

  11. 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. JNCI 1988; 80: 1451–61.

    PubMed  Google Scholar 

  12. McMannis JD, Fisher RI, Creekmore SP, Braun DP, Harris JE, Ellis TM.In vivo effects of recombinant IL 2. I. Isolation of circulating Leu-19 + lymphokine-activated effector cells from cancer patients receiving recombinant IL 2. J Immunol 1988; 140: 1335–40.

    PubMed  Google Scholar 

  13. Weil-Hillman G, Fisch P, Prieve AF, Sosman JA, Hank JA, Sondel PM. Lymphokine-activated killer activity induced by in vivo interleukin 2 therapy: Predominant role for lymphocytes with increased expression of CD2 and Leu 19 antigens but negative expression of CD16 antigens. Cancer Res 1989; 49: 3680–8.

    PubMed  Google Scholar 

  14. Sanders ME, Makgoba MW, Shaw S. Human naive and memory T cells. Immunology Today 1988; 9: 195–9.

    PubMed  Google Scholar 

  15. Mier JW, Vachino G, Van der Meer JWM, Numerof RP, Adams S, Cannon JG, Bernheim HA, Atkins MB, Parkinson DR, Dinarello CA. Induction of circulating tumor necrosis factor (TNFa) as the mechanism for the febrile response to interleukin-2 (IL -2) in cancer patients. J Clin Immunol 1988; 8: 426–36.

    PubMed  Google Scholar 

  16. Gemlo BT, Palladino MA Jr, Jaffe HS, Espevik TP, Rayner AA. Circulating cytokines in patients with metastatic cancer treated with recombinant interleukin 2 and lymphokineactivated killer cells. Cancer Res 1988; 48: 5864–7.

    PubMed  Google Scholar 

  17. Heslop HE, Gottlieb DJ, Bianchi ACM, Meager A, Prentice HG, Mehta AB, Hoffbrand AV, Brenner MK.In vivo induction of gamma interferon and tumor necrosis factor by interleukin-2 infusion following intensive chemotherapy or autologous marrow transplantation. Blood 1989; 74: 1374–80.

    PubMed  Google Scholar 

  18. Lotze MT, Matory YL, Ettinghausen SE, Rayner AA, Sharrow SO, Seipp CA, Custer MC, Rosenberg SA.In vivo administration of purified interleukin 2. II. Half-life, immunologic effects and expansion of peripheral lymphoid cellsin vivo with recombinant IL 2. J Immunol 1985; 135: 2865–75.

    PubMed  Google Scholar 

  19. Brown RR, Lee CM, Kohler PC, Hank JA, Storer BE, Sondel PM. Altered tryptophan and neopterin metabolism in cancer patients treated with recombinant interleukin 2. Cancer Res 1989; 49: 4941–4.

    PubMed  Google Scholar 

  20. Owen-Schaub LB, Gutterman JU, Grimm EA. Synergy of tumor necrosis factor and interleukin 2 in the activation of human cytotoxic lymphocytes: effect of tumor necrosis factor alpha and interleukin 2 in the generation of human lymphokine-activated killer cell cytotoxicity. Cancer Res 1988; 48: 788–92.

    PubMed  Google Scholar 

  21. Matossian-Rogers A, Browne C, Turkish M, O'Byrne P, Festenstein H. Tumour necrosis factor-alpha enhances the cytolytic and cytostatic capacity of interleukin-2 activated killer cells. Br J Cancer 1989; 59: 573–7.

    PubMed  Google Scholar 

  22. Scheurich P, Thoma B, Ücer U, Pfizenmaier K. Immunoregulatory activity of recombinant human tumor necrosis factor (TNI2)-α: induction of TNF receptors on human T cells and TNF-α-mediated enhancement of T cell responses. J Immunol 1987; 138: 1786–90.

    PubMed  Google Scholar 

  23. Blay J-Y, Favrot MC, Negrier S, Combaret V, Chouaib S, Mercatello A, Kaemmerlen P, Franks CR, Philip T. Correlation between clinical response to interleukin 2 therapy and sustained production of tumor necrosis factor. Cancer Res 1990; 50: 2371–4.

    PubMed  Google Scholar 

  24. Dupere S, Obiri N, Lackey A, Emma D, Yanelli J, Orr D, Birch R, O'Connor TE. Patterns of cytokines released by peripheral blood leukocytes of normal donors and cancer patients during interleukin 2 activationin vitro. J Biol Resp Modifiers 1990; 9: 140–8.

    Google Scholar 

  25. Yamaguchi S, Onji M, Kondoh H, Miyaoka H, Ohta Y. Immunologic effects on peripheral lymphoid cells from patients with chronic hepatitis type B during administration of recombinant interleukin 2. Clin Exp Immunol 1988; 74: 1–6.

    PubMed  Google Scholar 

  26. Kedar E, Rezai AR, Giorgi JV, Gale RP, Champlin RE, Mitsuyasu RT, Fahey JL. Immunomodulating effectsin vitro of interleukin 2 and interferon-gamma on human blood and bone marrow mononuclear cells. Nat Immun Cell Growth Regul 1988; 7: 13–30.

    PubMed  Google Scholar 

  27. Punnonen J, Viljanen MK. Recombinant interleukin 2 inhibits pokeweed mitogen-induced proliferation of human adult peripheral blood and cord blood mononuclear cells. Immunol Lett 1988; 18: 231–6.

    PubMed  Google Scholar 

  28. Duclos H, Maillot MC, Galanaud P. Interleukin induction of non-specific suppressor cells. AIPI 1986; 137: 3–10.

    Google Scholar 

  29. Ting CC, Yang SS, Hargrove ME. Induction of suppressor T cells by interleukin 2. J Immunol 1984; 133: 261–6.

    PubMed  Google Scholar 

  30. Pawelec G, Schneider EM, Rehbein A, Balko I, Wernet P. Dissection of suppressor cell generationin vitro. Human Immunology 1986; 17: 343–54.

    PubMed  Google Scholar 

  31. Hank JA, Sosman JA, Kohler PC, Bechhofer R, Storer B, Sondel PM. Depressedin vitro T cell responses concomitant with augmented interleukin-2 responses by lymphocytes from cancer patients followingin vivo treatment with interleukin-2. J Biol Response Mod 1990; 9: 5–14.

    PubMed  Google Scholar 

  32. Snydman DR, Sullivan B, Gill M, Gould JA, Parkinson DR, Atkins MB. Nosocomial sepsis associated with interleukin-2. Ann Intern Med 1990; 112: 102–7.

    PubMed  Google Scholar 

  33. Ebihara T, Koyama S, Fukao K, Osuga T. Lymphokineactivated suppressor (LAS) cells in patients with gastric carcinoma. Cancer Immunol Immunother 1989; 28: 218–24.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pawelec, G., Lenz, HJ., Schneider, E. et al. Clinical trial of natural human lymphocyte-derived interleukin 2 in cancer patients: Effects on cytokine production and suppressor cell status. Biotherapy 3, 309–318 (1991). https://doi.org/10.1007/BF02221323

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02221323

Key words

Navigation