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. 1982 Apr 1;155(4):968–980. doi: 10.1084/jem.155.4.968

Augmentation of the anti-tumor therapeutic efficacy of long-term cultured T lymphocytes by in vivo administration of purified interleukin 2

PMCID: PMC2186656  PMID: 6977616

Abstract

Spleen cells from C57BL/6 mice immunized in vivo with a syngeneic Friend virus-induced leukemia, FBL-3, were specifically activated by culture for 7 d with FBL-3, then nonspecifically induced to proliferate in vitro for 12 d by addition of supernatants from concanavalin A- stimulated lymphocytes containing interleukin 2 (IL-2). Such long-term cultured T lymphocytes have previously been shown to specifically lyse FBL-3 and to mediate specific adoptive therapy of advanced disseminated FBL-3 when used as an adjunct to cyclophosphamide (CY) in adoptive chemoimmunotherapy. Because the cultured cells are dependent upon IL-2 for proliferation and survival in vitro, their efficacy in vivo is potentially limited by the availability of endogenous IL-2. Thus, the aim of the current study was to determine whether exogenously administered purified IL-2 could augment the in vivo efficacy of long- term cultured T lymphocytes. Purified IL-2 alone or as an adjunct to CY as ineffective in tumor therapy. However, IL-2 was extremely effective in augmenting the efficacy of IL-2-dependent long-term cultured T lymphocytes in adoptive chemoimmunotherapy. The mechanism by which IL-2 functions in vivo is presumably by promoting in vivo growth and/or survival of adoptively transferred cells. This assumption was supported by the findings that IL-2 did not enhance the modest therapeutic efficacy of irradiated long-term cultured cells that were incapable of proliferating in the host and was ineffective in augmenting the in vivo efficacy of noncultured immune cells that are not immediately dependent upon exogenous IL-2 for survival.

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Selected References

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  1. Bernstein I. D., Cohen E. F., Wright P. W. Relationship of cellular proliferation and the generation of cytotoxic cells in an in vitro secondary immune response to syngeneic rat lymphoma cells. J Immunol. 1977 Mar;118(3):1090–1094. [PubMed] [Google Scholar]
  2. Cheever M. A., Greenberg P. D., Fefer A. Specific adoptive therapy of established leukemia with syngeneic lymphocytes sequentially immunized in vivo and in vitro and nonspecifically expanded by culture with Interleukin 2. J Immunol. 1981 Apr;126(4):1318–1322. [PubMed] [Google Scholar]
  3. Cheever M. A., Greenberg P. D., Fefer A. Specificity of adoptive chemoimmunotherapy of established syngeneic tumors. J Immunol. 1980 Aug;125(2):711–714. [PubMed] [Google Scholar]
  4. Cheever M. A., Greenberg P. D., Fefer A. Tumor neutralization, immunotherapy, and chemoimmunotherapy of a Friend leukemia with cells secondarily sensitized in vitro: II. Comparison of cells cultured with and without tumor to noncultured immune cells. J Immunol. 1978 Dec;121(6):2220–2227. [PubMed] [Google Scholar]
  5. Cheever M. A., Kempf R. A., Fefer A. Tumor neutralization, immunotherapy, and chemoimmmunotherapy of a Friend leukemia with cells secondarily sensitized in vitro. J Immunol. 1977 Aug;119(2):714–718. [PubMed] [Google Scholar]
  6. Fefer A., Einstein A. B., Jr, Cheever M. A., Berenson J. R. Models for syngeneic adoptive chemoimmunotherapy of murine leukemias. Ann N Y Acad Sci. 1976;276:573–583. doi: 10.1111/j.1749-6632.1976.tb41684.x. [DOI] [PubMed] [Google Scholar]
  7. Fefer A., McCoy J. L., Glynn J. P. Antigenicity of a virus-induced murine sarcoma (Moloney). Cancer Res. 1967 May;27(5):962–967. [PubMed] [Google Scholar]
  8. Fernandez-Cruz E., Halliburton B., Feldman J. D. In vivo elimination by specific effector cells of an established syngeneic rat moloney virus-induced sarcoma. J Immunol. 1979 Oct;123(4):1772–1777. [PubMed] [Google Scholar]
  9. Friedman H., Secter S., Kamo I., Kateley J. Tumor-associated immunosuppressive factors. Ann N Y Acad Sci. 1976;276:417–430. doi: 10.1111/j.1749-6632.1976.tb41667.x. [DOI] [PubMed] [Google Scholar]
  10. Fujimoto S., Greene M. I., Sehon A. H. Regualtion of the immune response to tumor antigens. I. Immunosuppressor cells in tumor-bearing hosts. J Immunol. 1976 Mar;116(3):791–799. [PubMed] [Google Scholar]
  11. GEHAN E. A. A GENERALIZED WILCOXON TEST FOR COMPARING ARBITRARILY SINGLY-CENSORED SAMPLES. Biometrika. 1965 Jun;52:203–223. [PubMed] [Google Scholar]
  12. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  13. Gillis S., Scheid M., Watson J. Biochemical and biologic characterization of lymphocyte regulatory molecules. III. The isolation and phenotypic characterization of Interleukin-2 producing T cell lymphomas. J Immunol. 1980 Dec;125(6):2570–2578. [PubMed] [Google Scholar]
  14. Gillis S., Smith K. A. Long term culture of tumour-specific cytotoxic T cells. Nature. 1977 Jul 14;268(5616):154–156. doi: 10.1038/268154a0. [DOI] [PubMed] [Google Scholar]
  15. Gillis S., Smith K. A., Watson J. Biochemical characterization of lymphocyte regulatory molecules. II. Purification of a class of rat and human lymphokines. J Immunol. 1980 Apr;124(4):1954–1962. [PubMed] [Google Scholar]
  16. Greenberg P. D., Cheever M. A., Fefer A. Detection of early and delayed antitumor effects following curative adoptive chemoimmunotherapy of established leukemia. Cancer Res. 1980 Dec;40(12):4428–4432. [PubMed] [Google Scholar]
  17. Greenberg P. D., Cheever M. A., Fefer A. Eradication of disseminated murine leukemia by chemoimmunotherapy with cyclophosphamide and adoptively transferred immune syngeneic Lyt-1+2- lymphocytes. J Exp Med. 1981 Sep 1;154(3):952–963. doi: 10.1084/jem.154.3.952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hardt C., Röllinghoff M., Pfizenmaier K., Mosmann H., Wagner H. Lyt-23+ cyclophosphamide-sensitive T cells regulate the activity of an interleukin 2 inhibitor in vivo. J Exp Med. 1981 Aug 1;154(2):262–274. doi: 10.1084/jem.154.2.262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hellström K. E., Hellström I. Lymphocyte-mediated cytotoxicity and blocking serum activity to tumor antigens. Adv Immunol. 1974;18:209–277. doi: 10.1016/s0065-2776(08)60311-9. [DOI] [PubMed] [Google Scholar]
  20. Lafferty K. J., Warren H. S., Woolnough J. A., Talmage D. W. Immunological induction of T lymphocytes: role of antigen and the lymphocyte costimulator. Blood Cells. 1978;4(3):395–406. [PubMed] [Google Scholar]
  21. Mochizuki D. Y., Watson J., Gillis S. Biochemical separation of interleukin 2. J Immunol Methods. 1980;39(3):185–201. doi: 10.1016/0022-1759(80)90055-1. [DOI] [PubMed] [Google Scholar]
  22. Mochizuki D., Watson J., Gillis S. Biochemical and biologic characterization of lymphocyte regulatory molecules. IV. Purification of Interleukin 2 from a murine T cell lymphoma. J Immunol. 1980 Dec;125(6):2579–2583. [PubMed] [Google Scholar]
  23. Plata F., Jongeneel C. V. Characterization to effector lymphocytes associated with immunity to murine sarcoma virus (MSV)-induced tumors. II. Repeated stimulation and proliferation in vitro of specific cytolytic T lymphocytes. J Immunol. 1977 Aug;119(2):623–629. [PubMed] [Google Scholar]
  24. Rosenberg S. A., Schwarz S., Spiess P. J. In vitro growth of murine T cells. II. Growth of in vitro sensitized cells cytotoxic for alloantigens. J Immunol. 1978 Nov;121(5):1951–1955. [PubMed] [Google Scholar]
  25. Rosenberg S. A., Terry W. D. Passive immunotherapy of cancer in animals and man. Adv Cancer Res. 1977;25:323–388. doi: 10.1016/s0065-230x(08)60637-5. [DOI] [PubMed] [Google Scholar]
  26. Ruscetti F. W., Morgan D. A., Gallo R. C. Functional and morphologic characterization of human T cells continuously grown in vitro. J Immunol. 1977 Jul;119(1):131–138. [PubMed] [Google Scholar]
  27. Ryser J. E., Cerottini J. C., Brunner K. T. Cell-mediated immunity to antigens associated with murine sarcoma virus-induced tumors: augmentation of cytolytic T lymphocyte activity by successive specific and nonspecific stimulation in vitro. Eur J Immunol. 1979 Mar;9(3):179–184. doi: 10.1002/eji.1830090302. [DOI] [PubMed] [Google Scholar]
  28. Smith K. A., Gillis S., Baker P. E., McKenzie D., Ruscetti F. W. T-cell growth factor-mediated T-cell proliferation. Ann N Y Acad Sci. 1979;332:423–432. doi: 10.1111/j.1749-6632.1979.tb47136.x. [DOI] [PubMed] [Google Scholar]
  29. Ting C. C., Shiu G., Rodrigues D., Herberman R. B. Cell-mediated immunity to Friend virus-induced leukemia. Cancer Res. 1974 Jul;34(7):1684–1687. [PubMed] [Google Scholar]
  30. Treves A. J., Cohen I. R., Feldman M. Immunotherapy of lethal metastases by lymphocytes sensitized against tumor cells in vitro. J Natl Cancer Inst. 1975 Mar;54(3):777–780. [PubMed] [Google Scholar]
  31. Wagner H., Hardt C., Heeg K., Pfizenmaier K., Solbach W., Bartlett R., Stockinger H., Röllinghoff M. T-T cell interactions during cytotoxic T lymphocyte (CTL) responses: T cell derived helper factor (Interleukin 2) as a probe to analyze CTL responsiveness and thymic maturation of CTL progenitors. Immunol Rev. 1980;51:215–255. doi: 10.1111/j.1600-065x.1980.tb00323.x. [DOI] [PubMed] [Google Scholar]
  32. Wagner H., Hardt C., Heeg K., Röllinghoff M., Pfizenmaier K. T-cell-derived helper factor allows in vivo induction of cytotoxic T cells in nu/nu mice. Nature. 1980 Mar 20;284(5753):278–278. doi: 10.1038/284278a0. [DOI] [PubMed] [Google Scholar]
  33. Wagner H., Röllinghoff M. T-T-cell interactions during the vitro cytotoxic allograft responses. I. Soluble products from activated Lyl+ T cells trigger autonomously antigen-primed Ly23+ T cells to cell proliferation and cytolytic activity. J Exp Med. 1978 Dec 1;148(6):1523–1538. doi: 10.1084/jem.148.6.1523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Watson J. Continuous proliferation of murine antigen-specific helper T lymphocytes in culture. J Exp Med. 1979 Dec 1;150(6):1510–1519. doi: 10.1084/jem.150.6.1510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Watson J., Gillis S., Marbrook J., Mochizuki D., Smith K. A. Biochemical and biological characterization of lymphocyte regulatory molecules. I. Purification of a class of murine lymphokines. J Exp Med. 1979 Oct 1;150(4):849–861. doi: 10.1084/jem.150.4.849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Weiss S., Dennert G. T cell lines active in the delayed-type hypersensitivity reaction (DTH). J Immunol. 1981 May;126(5):2031–2035. [PubMed] [Google Scholar]
  37. Zarling J. M., Bach F. H. Continuous culture of T cells cytotoxic for autologous human leukaemia cells. Nature. 1979 Aug 23;280(5724):685–688. doi: 10.1038/280685a0. [DOI] [PubMed] [Google Scholar]

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