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. 1985 May 1;161(5):1169–1188. doi: 10.1084/jem.161.5.1169

Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2

PMCID: PMC2187617  PMID: 3886826

Abstract

Incubation of resting lymphoid cells with recombinant interleukin 2 (IL- 2) in vitro leads to the generation of lymphokine activated killer (LAK) cells capable of lysing fresh tumor cell suspensions in short- term chromium-release assays. Our previous studies (7) have demonstrated that the injection of LAK cells plus low doses of recombinant IL-2 were capable of inhibiting the growth of pulmonary metastases. We have now explored the ability of high doses of recombinant IL-2, administered systemically, to generate LAK cells in vivo, and to mediate antitumor effects directly. Administration of increasing doses of recombinant IL-2 intraperitoneally resulted in the generation of LAK cells in the spleens of recipient mice. Doses of 100,000 U recombinant IL-2 administered intraperitoneally approximately every 8 h for 5 d were capable of dramatically inhibiting established 3- d pulmonary metastases from the MCA-105 and MCA-106 syngeneic sarcomas and the syngeneic B16 melanoma in C57BL/6 mice. Grossly visible metastases present at 10 d after tumor injection also underwent regression following IL-2 therapy. Surprisingly, established 10 d pulmonary metastases were more susceptible to the effects of IL-2 than were the smaller 3 d pulmonary metastases. All antitumor effects of the systemic administration of recombinant IL-2 were eliminated if mice received prior treatment with 500 rad total body irradiation. The administration of high doses of recombinant IL-2 was also capable of inhibiting the growth of 3-d established subcutaneous tumors from the MCA-105 sarcoma, and of mediating the inhibition of growth and regression of established palpable subcutaneous MCA-105 sarcomas. Lymphocytes, which appeared morphologically to be activated, were present at the site of regressing tumor, and it appears that the mechanism of the antitumor effect of recombinant IL-2 administered systemically is via the generation of LAK cells in vivo, although this hypothesis remains to be proven. The ready availability of high doses of recombinant human IL-2, and the demonstration of antitumor effects seen in animal models have led us to the initiation of the clinical trials of recombinant IL-2 in humans.

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Selected References

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  1. Chang A. E., Hyatt C. L., Rosenberg S. A. Systemic administration of recombinant human interleukin-2 in mice. J Biol Response Mod. 1984 Oct;3(5):561–572. [PubMed] [Google Scholar]
  2. Cheever M. A., Greenberg P. D., Fefer A., Gillis S. Augmentation of the anti-tumor therapeutic efficacy of long-term cultured T lymphocytes by in vivo administration of purified interleukin 2. J Exp Med. 1982 Apr 1;155(4):968–980. doi: 10.1084/jem.155.4.968. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Clason A. E., Duarte A. J., Kupiec-Weglinski J. W., Williams J. N., Wang B. S., Strom T. B., Tilney N. L. Restoration of allograft responsiveness in B rats by interleukin 2 and/or adherent cells. J Immunol. 1982 Jul;129(1):252–259. [PubMed] [Google Scholar]
  4. Donohue J. H., Rosenberg S. A. The fate of interleukin-2 after in vivo administration. J Immunol. 1983 May;130(5):2203–2208. [PubMed] [Google Scholar]
  5. Donohue J. H., Rosenstein M., Chang A. E., Lotze M. T., Robb R. J., Rosenberg S. A. The systemic administration of purified interleukin 2 enhances the ability of sensitized murine lymphocytes to cure a disseminated syngeneic lymphoma. J Immunol. 1984 Apr;132(4):2123–2128. [PubMed] [Google Scholar]
  6. GEHAN E. A. A GENERALIZED WILCOXON TEST FOR COMPARING ARBITRARILY SINGLY-CENSORED SAMPLES. Biometrika. 1965 Jun;52:203–223. [PubMed] [Google Scholar]
  7. Grimm E. A., Mazumder A., Zhang H. Z., Rosenberg S. A. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med. 1982 Jun 1;155(6):1823–1841. doi: 10.1084/jem.155.6.1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Grimm E. A., Ramsey K. M., Mazumder A., Wilson D. J., Djeu J. Y., Rosenberg S. A. Lymphokine-activated killer cell phenomenon. II. Precursor phenotype is serologically distinct from peripheral T lymphocytes, memory cytotoxic thymus-derived lymphocytes, and natural killer cells. J Exp Med. 1983 Mar 1;157(3):884–897. doi: 10.1084/jem.157.3.884. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Handa K., Suzuki R., Matsui H., Shimizu Y., Kumagai K. Natural killer (NK) cells as a responder to interleukin 2 (IL 2). II. IL 2-induced interferon gamma production. J Immunol. 1983 Feb;130(2):988–992. [PubMed] [Google Scholar]
  10. Hefeneider S. H., Conlon P. J., Henney C. S., Gillis S. In vivo interleukin 2 administration augments the generation of alloreactive cytolytic T lymphocytes and resident natural killer cells. J Immunol. 1983 Jan;130(1):222–227. [PubMed] [Google Scholar]
  11. Kawase I., Brooks C. G., Kuribayashi K., Olabuenaga S., Newman W., Gillis S., Henney C. S. Interleukin 2 induces gamma-interferon production: participation of macrophages and NK-like cells. J Immunol. 1983 Jul;131(1):288–292. [PubMed] [Google Scholar]
  12. Lotze M. T., Grimm E. A., Mazumder A., Strausser J. L., Rosenberg S. A. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. Cancer Res. 1981 Nov;41(11 Pt 1):4420–4425. [PubMed] [Google Scholar]
  13. Mazumder A., Grimm E. A., Rosenberg S. A. Lysis of fresh human solid tumor cells by autologous lymphocytes activated in vitro by allosensitization. Cancer Immunol Immunother. 1983;15(1):1–10. doi: 10.1007/BF00199454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Mazumder A., Grimm E. A., Zhang H. Z., Rosenberg S. A. Lysis of fresh human solid tumors by autologous lymphocytes activated in vitro with lectins. Cancer Res. 1982 Mar;42(3):913–918. [PubMed] [Google Scholar]
  15. Mazumder A., Rosenberg S. A. Successful immunotherapy of natural killer-resistant established pulmonary melanoma metastases by the intravenous adoptive transfer of syngeneic lymphocytes activated in vitro by interleukin 2. J Exp Med. 1984 Feb 1;159(2):495–507. doi: 10.1084/jem.159.2.495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Merluzzi V. J., Kenney R. E., Schmid F. A., Choi Y. S., Faanes R. B. Recovery of the in vivo cytotoxic T-cell response in cyclophosphamide-treated mice by injection of mixed-lymphocyte-culture supernatants. Cancer Res. 1981 Sep;41(9 Pt 1):3663–3665. [PubMed] [Google Scholar]
  17. Morgan D. A., Ruscetti F. W., Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science. 1976 Sep 10;193(4257):1007–1008. doi: 10.1126/science.181845. [DOI] [PubMed] [Google Scholar]
  18. Mulé J. J., Shu S., Schwarz S. L., Rosenberg S. A. Adoptive immunotherapy of established pulmonary metastases with LAK cells and recombinant interleukin-2. Science. 1984 Sep 28;225(4669):1487–1489. doi: 10.1126/science.6332379. [DOI] [PubMed] [Google Scholar]
  19. Pearlstein K. T., Palladino M. A., Welte K., Vilcek J. Purified human interleukin-2 enhances induction of immune interferon. Cell Immunol. 1983 Aug;80(1):1–9. doi: 10.1016/0008-8749(83)90088-6. [DOI] [PubMed] [Google Scholar]
  20. Reimann J., Diamantstein T. Interleukin-2 allows in vivo induction of anti-erythrocyte autoantibody production in nude mice associated with the injection of rat erythrocytes. Clin Exp Immunol. 1981 Mar;43(3):641–644. [PMC free article] [PubMed] [Google Scholar]
  21. Robb R. J., Munck A., Smith K. A. T cell growth factor receptors. Quantitation, specificity, and biological relevance. J Exp Med. 1981 Nov 1;154(5):1455–1474. doi: 10.1084/jem.154.5.1455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Rosenberg S. A., Grimm E. A., McGrogan M., Doyle M., Kawasaki E., Koths K., Mark D. F. Biological activity of recombinant human interleukin-2 produced in Escherichia coli. Science. 1984 Mar 30;223(4643):1412–1414. doi: 10.1126/science.6367046. [DOI] [PubMed] [Google Scholar]
  23. Rosenberg S. A., Spiess P. J., Schwarz S. In vitro growth of murine T cells. I. Production of factors necessary for T cell growth. J Immunol. 1978 Nov;121(5):1946–1950. [PubMed] [Google Scholar]
  24. Rosenberg S. A., Spiess P. J., Schwarz S. In vivo administration of Interleukin-2 enhances specific alloimmune responses. Transplantation. 1983 Jun;35(6):631–634. doi: 10.1097/00007890-198306000-00024. [DOI] [PubMed] [Google Scholar]
  25. Rosenstein M., Yron I., Kaufmann Y., Rosenberg S. A. Lymphokine-activated killer cells: lysis of fresh syngeneic natural killer-resistant murine tumor cells by lymphocytes cultured in interleukin 2. Cancer Res. 1984 May;44(5):1946–1953. [PubMed] [Google Scholar]
  26. Strausser J. L., Mazumder A., Grimm E. A., Lotze M. T., Rosenberg S. A. Lysis of human solid tumors by autologous cells sensitized in vitro to alloantigens. J Immunol. 1981 Jul;127(1):266–271. [PubMed] [Google Scholar]
  27. Stötter H., Rüde E., Wagner H. T cell factor (interleukin 2) allows in vivo induction of T helper cells against heterologous erythrocytes in athymic (nu/nu) mice. Eur J Immunol. 1980 Sep;10(9):719–722. doi: 10.1002/eji.1830100912. [DOI] [PubMed] [Google Scholar]
  28. Wexler H. Accurate identification of experimental pulmonary metastases. J Natl Cancer Inst. 1966 Apr;36(4):641–645. doi: 10.1093/jnci/36.4.641. [DOI] [PubMed] [Google Scholar]
  29. Yron I., Wood T. A., Jr, Spiess P. J., Rosenberg S. A. In vitro growth of murine T cells. V. The isolation and growth of lymphoid cells infiltrating syngeneic solid tumors. J Immunol. 1980 Jul;125(1):238–245. [PubMed] [Google Scholar]
  30. Zarling J. M., Robins H. I., Raich P. C., Bach F. H., Bach M. L. Generation of cytotoxic T lymphocytes to autologous human leukaemia cells by sensitisation to pooled allogeneic normal cells. Nature. 1978 Jul 20;274(5668):269–271. doi: 10.1038/274269a0. [DOI] [PubMed] [Google Scholar]
  31. Zielske J. V., Golub S. H. Fetal calf serum-induced blastogenic and cytotoxic responses of human lymphocytes. Cancer Res. 1976 Oct;36(10):3842–3846. [PubMed] [Google Scholar]

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