Cancer Immunology, Immunotherapy

, Volume 35, Issue 1, pp 27–32 | Cite as

Antitumour efficacy of lymphokine-activated killer cells loaded with ricin against experimentally induced lung metastases

  • Paola Zanovello
  • Antonio Rosato
  • Vincenzo Bronte
  • Susanna Mandruzzato
  • Vincenzo Cerundolo
  • Dino Collavo
Original articles


Adoptive transfer of tumour-specific T lymphocytes loaded with ricin into tumour-bearing mice exerts a transient therapeutic effect against locally induced tumours [Cerundolo et al. (1987) Br J Cancer 55: 413]. As transferred cells preferentially locate in the lung, we studied the therapeutic effect of ricin-loaded, lymphokine-activated killer (LAK) cells on lung metastases induced by M4 or B16-F1 (F1) tumour cell injection. In vitro studies demonstrated that ricin-treated LAK cells were about 100-fold more efficient than untreated LAK cells in inhibiting growth of the ricin-sensitive M4 tumour cell line. This effect was most likely due to the released ricin, as treated and untreated LAK cells inhibited the relatively toxin-resistant F1 cell line to the same extent. Ricin treatment did not alter the tissue distribution of intravenously (i.v.) injected LAK cells, which selectively localized in the lung early after inoculation, whether or not metastases were present. Adoptive transfer experiments showed that ricintreated LAK cells were significantly more efficient than untreated LAK cells in inhibiting M4- but not F1-induced lung metastases. These results indicate that LAK cells are able to deliver a therapeutic concentration of antineoplastic compounds directly to the lung.

Key words

LAK cells Ricin Lung metastases 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Barbieri L, Stirpe F (1982) Ribosome inactivating proteins from plants: properties and possible uses. Cancer Surv 1: 489Google Scholar
  2. 2.
    Basse P, Herberman RB, Nannmark U, Johansson BR, Hokland M, Wasserman K, Goldfarb RH (1991) Accumulation of adoptively adherent lymphokine-activated killer cells in murine metastases. J Exp Med 174: 479Google Scholar
  3. 3.
    Bonmassar E, Houchens DP, Fioretti MC, Goldin A (1975) Uptake of 5-iododeoxyuridine as a measure of tumor growth and tumor inhibition. Chemotherapy 21: 321Google Scholar
  4. 4.
    Carrol AM, Palladino MA, Gettgen H, De Sousa M (1983) In vivo localization of cloned IL-2 dependent T cells. Cell Immunol 76: 69Google Scholar
  5. 5.
    Cerundolo V, Lahaye T, Horvath C, Zanovello P, Collavo D, Engers HD (1987) Functional activity in vivo of effector T cell populations: III. Protection against Moloney murine sarcoma virus (M-MSV)-induced tumors in T cell deficient mice by the adoptive transfer of M-MSV-specific cytolytic T lymphocyte clone. Eur J Immunol 17: 173Google Scholar
  6. 6.
    Cerundolo V, Zanovello P, McIntosh D, Fabbris R, Davies AJS, Collavo D (1987) Temporary inhibition of Moloney-murine sarcoma virus (M-MSV) induced-tumours by adoptive transfer of ricintreated T-lymphocytes. Br J Cancer 55: 413Google Scholar
  7. 7.
    Collavo D, Parenti A, Biasi G, Chieco Bianchi L, Colombatti A (1978) Secondary in vitro generation of cytolytic T-lymphocytes (CTLs) in the murine sarcoma virus system. Virus-specific CTL induction across the H-2 barrier. J Natl Cancer Inst 61: 885Google Scholar
  8. 8.
    Dailey MO, Fathman GC, Butcher EC, Pillemer E, Weissman I (1982) Abnormal migration of T lymphocytes clones. J Immunol 128: 2134Google Scholar
  9. 9.
    De Flora A, Benatti U, Guida L, Zocchi E (1986) Encapsulation of Adriamycin in human erythrocytes. Proc Natl Acad Sci USA 83: 7029Google Scholar
  10. 10.
    Felgar RE, Hiserodt J (1990) In vivo migration and tissue localization of highly purified lymphokine-activated killer cells (A-LAK cells) in tumor-bearing rats. Cell Immunol 129: 288Google Scholar
  11. 11.
    Fidler IJ (1973) Selection of successive tumor lines for metastases. Nature 242: 148Google Scholar
  12. 12.
    Gabizon A, Papahadjopoulos D (1988) Liposome formulation with prolonged circulation time in blood and enhanced uptake by tumors. Proc Natl Acad Sci USA 85: 6949Google Scholar
  13. 13.
    Gregoriadis G, Senior J, Wolff B, Kirby C (1985) Targeting of liposomes to accessible cells in vivo. Ann NY Acad Sci 446: 319Google Scholar
  14. 14.
    Hall J (1985) The study of circulating lymphocytes in vivo: a personal view of artifice and artifact. Immunol Today 5: 149Google Scholar
  15. 15.
    Hamann A, Jablonski-Westrich D, Scholz KW, Duijvestijn A, Butcher EC, Thiele HG (1988) Regulation of lymphocyte homing: I. Alterations in homing receptor expression and organ-specific high endothelial venule binding of lymphocytes upon activation. J Immunol 140: 737Google Scholar
  16. 16.
    Huang A, Kennel SJ, Huang L (1983) Interactions of immunoliposomes with target cells. J Biol Chem 258: 14034Google Scholar
  17. 17.
    Lafreniere R, Rosenberg SA (1985) Successful immunotherapy of murine experimental hepatic metastases with lymphokine-activated killer cells and recombinant interleukin-2. Cancer Res 45: 3735Google Scholar
  18. 18.
    Leserman LD, Barbet J, Kourilsky F, Weinstein JN (1981) Cell-specific drug transfer from liposomes bearing monoclonal antibodies. Nature 293: 226Google Scholar
  19. 19.
    Lotze MT, Line BR, Mathiesen DJ, Rosenberg SA (1980) The in vivo distribution of autologous human and murine lymphoid cell grown in T cell growth factor (TCGF): implications for the adoptive immunotherapy of tumors. J Immunol 125: 1487Google Scholar
  20. 20.
    Maghazachi A, Fitzgibbon L (1990) Fate of intravenously administered rat lymphokine-activated killer cells labeled with different markers. Cancer Immunol Immunother 31: 139Google Scholar
  21. 21.
    Maghazachi AA, Herberman RB, Vujanovic NL, Hiserodt JC (1988) In vivo distribution and tissue localization of highly purified rat lymphokine-activated killer (LAK) cells. Cell Immunol 15: 179Google Scholar
  22. 22.
    Mantovani A, Giavazzi R, Alessandri G, Spreafico F, Garattini S (1981) Characterization of tumor lines derived from spontaneous metastases of a transplantated murine sarcoma. Eur J Cancer 17: 7Google Scholar
  23. 23.
    Matzku S, Krempel H, Weckenmann H-P, Schirrmacher V, Sinn H, Stricker H (1990) Tumour targeting with antibody-coupled liposomes: failure to achieve accumulation in xenografts and spontaneous metastases. Cancer Immunol Immunother 31: 285Google Scholar
  24. 24.
    McIntosh DP, Edwards DC, Davies AJS (1984) Transfer of ricin toxicity by spleen cells. Toxicon 22: 293Google Scholar
  25. 25.
    Mulé JJ, Shu S, Schwarz SL, Rosenberg SA (1984) Adoptive immunotherapy of established pulmonary metastases with LAK cells and recombinant interleukin-2. Science 255: 1487Google Scholar
  26. 26.
    Rodolfo M, Salvi C, Parmiani G (1989) Influence of the donor's clinical status on in vitro and in vivo tumor cytotoxic activation of interleukin-2-exposed lymphocytes and their circulation in different organs. Cancer Immunol Immunother 28: 136Google Scholar
  27. 27.
    Rosenberg SA (1985) Adoptive immunotherapy of cancer using lymphokine activated killer cells and recombinant interleukin-2. J Natl Cancer Inst 1: 55Google Scholar
  28. 28.
    Rosenberg SA (1988) Immunotherapy of patients with advanced cancer using interleukin-2 alone or in combination with lymphokine activated killer cells. In: Important advances in oncology. DeVita VT, Hellman S, Rosenberg SA (Eds) Lippincott, Philadelphia, p 217Google Scholar
  29. 29.
    Sprent J (1976) Fate of H2-activated T lymphocytes in syngeneic hosts: I Fate in lymphoid tissues and intestines traced with3H-thymidine,125I-deoxyuridine and51chromium. Cell Immunol 21: 278Google Scholar
  30. 30.
    Weinstein JN (1984) Liposomes as drug carriers in cancer therapy. Cancer Treat Rep 68: 127Google Scholar
  31. 31.
    Zocchi E, Tonetti M, Polvani C, Guida L, Benatti U, De Flora A (1989) Encapsulation of doxorubicin in liver-targeted erythrocytes increases the therapeutic index of the drug in a murine metastatic model. Proc Natl Acad Sci USA 86: 2040Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Paola Zanovello
    • 1
  • Antonio Rosato
    • 1
  • Vincenzo Bronte
    • 1
  • Susanna Mandruzzato
    • 1
  • Vincenzo Cerundolo
    • 1
  • Dino Collavo
    • 1
  1. 1.Chair of Immunology, Institute of OncologyInter-University Center for Cancer Research, University of PadovaPadovaItaly

Personalised recommendations