Skip to main content
SpringerLink
Log in

Adoptive immunotherapy of a mouse colon carcinoma with recombinant interleukin-2 alone or combined with lymphokine-activated killer cells or tumor-immune lymphocytes

Survival benefit of adjuvant post-surgical treatments and comparison with experimental metastases model

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

Summary

We have used a BALB/c colonic adenocarcinoma (C-26) to evaluate the therapeutic potential of recombinant interleukin-2 (rIL-2) at high and low dosages in combination with or without lymphokine-activated killers (LAK) or tumor-specific, immune lymphocytes in either an adjuvant spontaneous or an artificial metastasis system. Most (≈80%) of the mice that underwent s.c. C-26 tumor excision were shown to die of spontaneous metastasis with lung involvement by 1–4 months after excision. Postsurgical systemic treatment with low-dose rIL-2 (3 × 104 U/day, i.p.) increased the survival rate to 31% as compared to 21% (not significant) in excised controls while administration of high-dose rIL-2 (8 × 104 U/day) led to 53% survival (P <0.01). Both LAK cells and C-26-tumor-immune lymphocytes given during rIL-2 treatment significantly increased the effects of rIL-2 at the low but not at the high-dose, with tumor-immune effectors resulting in the highest percentage (63%) of cures. When mice bearing 3-day artificial lung metastases of C-26 cells were treated with low- or high-dose rIL-2, in combination with or without LAK or tumor-immune lymphocytes, a highly significant reduction or abrogation of the number of lung foci was observed with all treatments, including those involving or tumor-immune lymphocytes alone. Assessment of survival benefit in these mice, however, showed survival prolongation, with 20% cures achieved by low-dose rIL-2 alone and up to 65% cures by LAK in combination with low-dose rIL-2. In this system of artificial metastasis high-dose rIL-2 alone increased the survival time but failed to cure the animals, and the addition of LAK was ineffective whereas that of tumor-immune lymphocytes led to 80% cure. These results suggest that tumorimmune lymphocytes are more effective than LAK when combined with rIL-2 and that caution is necessary in extrapolating findings obtained in artificial metastasis models.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

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. Brattain MG, Strobel-Stevens J, Five D, Webb M, Sarrif AM (1980) Establishment of mouse colonic carcinoma cell lines with different metastatic properties. Cancer Res 40: 2142

    Google Scholar 

  2. Chou T, Chang AE, Shu S (1988) Generation of therapeutic T lymphocytes from tumor-bearing mice by in vitro sensitization. J Immunol 140: 2453

    Google Scholar 

  3. Colombo MP, Arioli I, Parmiani G (1985) Passive immunotherapy of a BALB/c lymphoma by syngeneic anti-DBA/2 immune lymphoid cells. Characterization of the effector population and evidence for the role of host's non T cells. Cancer Immunol Immunother 20: 198

    Google Scholar 

  4. Fisher B, Packard BS, Read EJ, Carasquillo JA, Carter CS, Topalian SL, Yang JC, Yolles P, Larson SM, Rosenberg SA (1989) Tumor localization of adoptively transferred indium-111 labeled tumor infiltrating lymphocytes in patients with metastatic melanoma. J Clin Oncol 7: 250

    Google Scholar 

  5. Greenberg PD, Kern DE, Cheever MA (1985) Therapy of disseminated murine leukemia with cyclophosphamide and immune Lyt1+2− T cells. Tumor eradication does not require participation of cytotoxic T cells. J Exp Med 161: 1122

    Google Scholar 

  6. Greenberg PD (1986) Therapy of murine leukemia with cyclophosphamide and immune Lyt 2+ cells: cytolytic T cells can mediate eradication of disseminated leukemia. J Immunol 136: 1917

    Google Scholar 

  7. Hosokawa M, Yabiku T, Ikeda J, Sawamura Y, Okada F, Komatsumoto M, Tanabe T, Kobayashi H (1988) Effects of a combination of cyclophosphamide and human recombinant interleukin 2 on pulmonary metastasis after the surgical removal of a 3-methylcholanthrene-induced primary tumor in autochthonous mice. Jpn J Cancer Res 79: 1147

    Google Scholar 

  8. Lafreniere R, Rosenberg SA (1985) Adoptive immunotherapy of murine hepatic metastases with lymphokine activated killer cells (LAK) and rIL-2 can mediate the regression of both immunogenic and nonimmunogenic sarcomas and an adenocarcinoma. J Immunol 135: 4273

    Google Scholar 

  9. Lotze MT, Chang AE, Seipp CA, Simpson C, Vetto JT, Rosenberg SA (1986) High dose recombinant interleukin 2 in the treatment of patients with disseminated cancer: responses, treatment-related morbidity, and histologic findings. J Am Med Assoc 256: 3117

    Google Scholar 

  10. Mazumder A, Rosenberg SA (1984) Successful immunotherapy of natural killer-resistant established pulmonary metastases by the intravenous adoptive transfer of syngeneic lymphocytes activated in vitro by recombinant interleukin 2. J Exp Med 159: 405

    Google Scholar 

  11. Mulé JJ, Ettinghausen SE, Spiess PJ, Shu S, Rosenberg SA (1986) Anti-tumor efficacy of lymphokine-activated killer cells and rIL-2 in vivo: survival benefit and mechanisms of tumor escape in mice undergoing immunotherapy. Cancer Res 46: 676

    Google Scholar 

  12. Mulé JJ, Yang J, Shu S, Rosenberg SA (1986) The antitumor efficacy of lymphokine activated killer cells and recombinant interleukin 2 in vivo: direct correlation between reduction of established metastases and cytolytic activity of lymphokine activated killer cells. J Immunol 136: 3899

    Google Scholar 

  13. Papa MZ, Mulé JJ, Rosenberg SA (1986) Antitumor efficacy of lymphokine-activated killer cells and recombinant interleukin-2 in vivo: successful immunotherapy of established pulmonary metastases from weakly immunogenic and nonimmunogenic murine tumors of three distinct histological types. Cancer Res 46: 4973

    Google Scholar 

  14. Peace DJ, Cheever MA (1989) Toxicity and therapeutic efficacy of high-dose interleukin 2. In vivo infusion of antibody to NK-1.1 attenuates toxicity without compromising efficacy against murine leukemia. J Exp Med 169: 161

    Google Scholar 

  15. Rodolfo M, Parmiani G (1987) Growth inhibition of murine colonic adenocarcinoma by tumor immune but not by rIL-2 activated or alloactivated lymphocytes. Tumori 73: 1

    Google Scholar 

  16. Rodolfo M, Salvi C, Parmiani G (1989) Influence of the donors' 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: 136

    Google Scholar 

  17. Rosenberg SA (1988) Immunotherapy of cancer using interleukin 2. Immunol Today 9: 58

    Google Scholar 

  18. Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, Simon P, Lotze MT, Yang JC, Seipp CA, Simpson C, Carter C, Bock S, Schwartzentruber D, Wei JP, White DE (1988) Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. N Engl J Med 319: 1676

    Google Scholar 

  19. Salup RR, Wiltrout RH (1986) Adjuvant immunotherapy of established murine renal cancer by interleukin 2-stimulated cytotoxic lymphocytes. Cancer Res 46: 3358

    Google Scholar 

  20. Schoof DD, Gramolini BA, Davidson DL, Massaro AF, Wilson RE, Eberlein TJ (1988) Adoptive immunotherapy of human cancer using low-dose recocmbinant interleukin 2 and lymphokine-activated killer cells. Cancer Res 48: 5007

    Google Scholar 

  21. Spiess PJ, Yang JC, Rosenberg SA (1987) In vivo antitumor activity of tumor infiltrating lymphocytes expanded in recombinant interleukin-2. J Natl Cancer Inst 79: 1067

    Google Scholar 

  22. Talmadge JE, Phillips H, Schindler J, Tribble H, Pennington R (1987) Systematic preclinical study on the therapeutic properties of recombinant human interleukin 2 for the treatment of metastatic disease. Cancer Res 47: 5725

    Google Scholar 

  23. Thompson JA, Peace DJ, Klarnet JP, Kern DE, Greenberg PD, Cheever MA (1986) Eradication of disseminated murine leukemia by treatment with high-dose interleukin 2. J Immunol 137: 3675

    Google Scholar 

  24. Treves AJ, Cohen IR, Feldmann M (1975) Immunotherapy of lethal metastases by lymphocytes sensitized against tumor cells in vitro. J Natl Cancer Inst 54: 777

    Google Scholar 

  25. Vaage J (1987) Local and systemic effects during interleukin-2 therapy of mouse mammary tumors. Cancer Res 47: 4296

    Google Scholar 

  26. Wang J, Walle A, Gordon B, Novogrodsky A, Suthanthiran M, Rubin A, Morrison H, Silver RT, Stenzel KH (1987) Adoptive immunotherapy for stage IV renal cell carcinoma: a novel protocol utilizing periodate and interleukin-2-activated autologous leukocytes and continous infusions of low-dose interleukin-2. Am J Med 83: 1016

    Google Scholar 

  27. West WH, Tauer KW, Yannelli JR, Marshakk JD, Orr DW, Thurmann GB, Oldham RK (1987) Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med 316: 898

    Google Scholar 

  28. Wexler H (1966) Accurate identification of experimental pulmonary metastasis. J Natl Cancer Inst 36: 641

    Google Scholar 

  29. Wiebke EA, Rosenberg JA, Lotze MT (1988) Acute immunologic effects of interleukin-2 therapy in cancer patients: decreased delayed hypersensitivity response and decreased proliferative response to soluble antigens. J Clin Oncol 6: 1440

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Experimental Oncology D, Istituto Nazionale Tumor, Via Venezian 1, I-20133, Milan, Italy

    Monica Rodolfo, Carolina Salvi, Cinzia Bassi & Giorgio Parmiani

Authors
  1. Monica Rodolfo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carolina Salvi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cinzia Bassi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Giorgio Parmiani
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rodolfo, M., Salvi, C., Bassi, C. et al. Adoptive immunotherapy of a mouse colon carcinoma with recombinant interleukin-2 alone or combined with lymphokine-activated killer cells or tumor-immune lymphocytes. Cancer Immunol Immunother 31, 28–36 (1990). https://doi.org/10.1007/BF01742492

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01742492

Keywords

Search

Navigation