Cancer Immunology, Immunotherapy

, Volume 35, Issue 1, pp 63–68 | Cite as

Chemo-Immunotherapy of murine solid tumors: Enhanced therapeutic effects by interleukin-2 combined with interferon α and the role of specific T cells

  • Eli Kedar
  • Yaron Rutkowski
  • Benny Leshem
Original articles


The aim of the present study has been to assess the therapeutic efficacy of various cytokines, singly or in combination, with and without chemotherapy (cyclophosphamide, Cy), in mice carrying advanced, weakly immunogenic tumors (MCA-105 sarcoma, M109 carcinoma). Treatment of animals with i.p. growths or experimental pulmonary metastases began 8–18 days after i.p. or i.v. tumor cell inoculation respectively. None of the cytokines tested [interleukin-2 (IL-2), interferon α (IFNα), tumor necrosis factor α (TNFα) and macrophage-colony-stimulating factor (M-CSF)] nor Cy had by itself a significant curative effect. A synergistic therapeutic effect was obtained with IL-2 or IFNα (but not with TNFα or M-CSF) in combination with Cy. The most efficacious regimen (65%–90% cure of mice carrying i.p. tumors) was the combination of Cy+IL-2+IFNα. Preliminary experiments suggested that sequential administration of these cytokines might be more beneficial than concurrent administration. Following successful immunotherapy, long-term (3–6 months) survivors showed a tumor-specific resistance to a second tumor challenge and their spleen contained an increased number of specific antitumor cytotoxic T lymphocyte precursors (5- to 20-fold, compared to control mice). In vitro and in vivo cell-depletion experiments using monoclonal antibodies revealed that T cells (primarily CD8), but not NK cells, are crucial for the therapeutic effects. This study indicates that a potent specific antitumor T cell immunity can be elicited against advanced weakly immunogenic tumors by combining chemotherapy (Cy) with IL-2 and IFNα.

Key words

Chemo-immunotherapy Cytokines T cells 


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  1. 1.
    Asher AL, Mulé JJ, Kasid A, Restifo NP, Salo JC, Reichert CM, Jaffe G, Fendly B, Kriegler M, Rosenberg SA (1991) Murine tumor cells transduced with the gene for tumor necrosis factor α. Evidence for paracrine immune effects of tumor necrosis factor against tumors. J Immunol 146: 3227Google Scholar
  2. 2.
    Atzpodien J, Körfer A, Franks CR, Poliwoda H, Kirchner H (1990) Home therapy with recombinant interleukin-2 and interferon-α2b in advanced human malignancies. Lancet 335: 1509Google Scholar
  3. 3.
    Balkwill FR (1989) Interferons. Lancet 1: 1060Google Scholar
  4. 4.
    Boldt DH, Mills BJ, Gemlo BT, Holden H, Mier J, Paietta E, McMannis JD, Escobedo LV, Sniecinski I, Rayner AA, Hawkins MJ, Atkins MB, Ciobanu N, Ellis TM (1988) Laboratory correlates of adoptive immunotherapy with recombinant interleukin-2 and lymphokine-activated killer cells in humans. Cancer Res 48: 4409Google Scholar
  5. 5.
    Borden EC (1988) Augmented tumor-associated antigen expression by interferons. J Natl Cancer Inst 80: 148Google Scholar
  6. 6.
    Borden EC, Sidky YA, Hatcher JF, Bryan GT (1988) Schedule-dependent variations in the response of murine P388 leukemia to cyclophosphamide in combination with interferons-α/β. Cancer Res 48: 2329Google Scholar
  7. 7.
    Brunda MJ, Bellantoni D, Sulich V (1987) In vivo anti-tumor activity of combinations of interferon alpha and interleukin-2 in a murine model. Correlation of efficacy with the induction of cytotoxic cells resembling natural killer cells. Int J Cancer 40: 365Google Scholar
  8. 8.
    Cameron RB, McIntosh JK, Rosenberg SA (1988) Synergistic antitumor effects of combination immunotherapy with recombinant interleukin-2 and recombinant hybrid α-interferon in the treatment of established murine hepatic metastases. Cancer Res 48: 5810Google Scholar
  9. 9.
    Dillman RO, Oldham RK, Tauer KW, Orr DW, Barth NM, Blumenschein G, Arnold J, Birch R, West WH (1991) Continuous interleukin-2 and lymphokine-activated killer cells for advanced cancer: a national biotherapy study group trial. J Clin Oncol 9: 1233Google Scholar
  10. 10.
    Elias L, Crissman HA (1988) Interferon effects upon the adenocarcinoma 38 and HL-60 cell lines: antiproliferative responses and synergistic interactions with halogenated pyrimidine antimetabolites. Cancer Res 48: 4868Google Scholar
  11. 11.
    Faltynek CR, Oppenheim JJ (1988) Interferons in host defense. J Natl Cancer Inst 80: 151Google Scholar
  12. 12.
    Foon KA (1989) Biological response modifiers: the new immunotherapy. Cancer Res 49: 1621Google Scholar
  13. 13.
    Ghosh AK, Dazzi H, Thatcher N, Moore M (1989) Lack of correlation between peripheral blood lymphokine-activated killer (LAK) cell function and clinical response in patients with advanced malignant melanoma receiving recombinant interleukin-2. Int J Cancer 43: 410Google Scholar
  14. 14.
    Greenberg PD (1991) Adoptive T cell therapy of tumors: Mechanisms operative in the recognition and elimination of tumor cells. Adv Immunol 49: 281Google Scholar
  15. 15.
    Hamblin TJ, Davies B, Sadullah S, Oskam R, Palmer P, Franks CR (1991) A phase II study of the treatment of metastatic malignant melanoma with a combination of dacarbazine, cis-platin, interleukin-2 and alfa-interferon (IFN) (abstract). Proc Am Soc Clin Oncol 10: 294Google Scholar
  16. 16.
    Hirsh M, Lipton A, Harvey H, Givant E, Hopper K, Jones G, Zeffren J, Levitt D (1990) Phase I study of interleukin-2 and interferon alpha-2a as outpatient therapy for patients with advanced malignancy. J Clin Oncol 8: 1657Google Scholar
  17. 17.
    Hosokawa M, Sawamura Y, Morikage T, Okada F, Xu ZY, Morikawa K, Itoh K, Kobayashi H (1988) Improved therapeutic effects of interleukin 2 after accumulation of lymphokine-activated killer cells in tumor tissue of mice previously treated with cyclophosphamide. Cancer Immunol Immunother 26: 250Google Scholar
  18. 18.
    Isacson R, Kedar E, Barak V, Gazit Z, Yurim O, Kalichman I, Ben-Basar H, Biran S, Schlesinger M, Franks CR, Roest G, Palmer P, Shiloni E (1991) Chemo-immunotherapy in patients with metastatic melanoma using sequential treatment with dacarbazine (DTIC) and recombinant human interleukin-2: evaluation of hematologic and immunologic parameters and correlation with clinical response (in press)Google Scholar
  19. 19.
    Kedar E, Klein E (1992) Cancer immunotherapy: are the results discouraging? Can they be improved? Adv Cancer Res (in press)Google Scholar
  20. 20.
    Kedar E, Ben-Aziz R, Shiloni E (1988) Therapy of advanced solid tumors in mice using chemotherapy in combination with interleukin-2 with and without lymphokine-activated killer cells. Israel J Med Sci 24: 494Google Scholar
  21. 21.
    Kedar E, Ben-Aziz R, Epstein E, Leshem B (1989) Chemo-immunotherapy of murine tumors using interleukin-2 (IL-2) and cyclophosphamide. IL-2 can facilitate or inhibit tumor growth depending on the sequence of treatment and the tumor type. Cancer Immunol Immunother 29: 74Google Scholar
  22. 22.
    Kedar E, Gazit-Lebendiker Z, Tsuberi B, Ben-Aziz R, Epstein E, Weisz A, Rutkowski Y, Shiloni E, Shouval D, Weiss DW, Leshem B, Slavin S (1990) Cytokines increase the therapeutic efficacy of cancer chemotherapy and facilitate reconstitution following bone marrow transplantation. In: Adam A, Rubinstein E (eds) Recent advances in chemotherapy. Lewin-Epstein, Bat-Yam, pp 840.1–840.8Google Scholar
  23. 23.
    Kinnon C, Levinsky RJ (1990) Gene therapy for cancer. Eur J Cancer 26: 638Google Scholar
  24. 24.
    Krosnick JA, Mulè JJ, McIntosh JK, Rosenberg SA (1989) Augmentation of antitumor efficacy by the combination of recombinant tumor necrosis factor and chemotherapeutic agents in vivo. Cancer Res 49: 3729Google Scholar
  25. 25.
    Leshem B, Kedar E (1990) Cytotoxic T lymphocytes reactive against a syngeneic murine tumor and their specific suppressor T cells are both elicited by in vitro allosensitization. J Exp Med 171: 1057Google Scholar
  26. 26.
    MacDonald HR, Cerottini JC, Ryser JE, Maryanski JL, Taswell C, Widmer MB, Brunner KT (1980) Quantitation and cloning of cytolytic T lymphocytes and their precursors. Immunol Rev 51: 93Google Scholar
  27. 27.
    Mitchell MS (1988) Combining chemotherapy with biological response modifiers in treatment of cancer. J Natl Cancer Inst 80: 1445Google Scholar
  28. 28.
    Parmiani G (1990) An explanation of the variable clinical response to interleukin-2 and LAK cells. Immunol Today 11: 113Google Scholar
  29. 29.
    Richards JM, Priest E, Hamasaki V, Skosey P, Ramming K (1991) Sequential chemoimmunotherapy for metastatic melanoma (abstract). Proc Am Soc Clin Oncol 10: 298Google Scholar
  30. 30.
    Rosenberg SA, Longo DL, Lotze MT (1989) Principles and applications of biologic therapy. In: DeVita VT, Hellman S, Rosenberg SA (eds) Cancer. Principles and practice of oncology, 3rd edn. Lippincott, Philadelphia, pp 301–347Google Scholar
  31. 31.
    Rosenberg SA, Lotze MT, Yang JC, Aebersold PM, Linehan WM, Seipp CA, White DE (1989) Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg 210: 474Google Scholar
  32. 32.
    Rosenberg SA, Lotze MT, Yang JC, Linehan WM, Seipp CA, Calabro S, Karp SE, Sherry RM, Steinberg S, White DE (1989) Combination therapy with interleukin-2 and alpha-interferon for the treatment of patients with advanced cancer. J Clin Oncol 7: 1863Google Scholar
  33. 33.
    Russell SJ (1990) Lymphokine gene therapy for cancer. Immunol Today 11: 196Google Scholar
  34. 34.
    Scala S, Murphy LD, Tortora G, Cho-Chung Y, Bates S (1991) Effects of differentiating agents (DA) on P-glycoprotein (Pgp) expression in a multidrug resistant breast cancer cell line (abstract). Proc Am Assoc Cancer Res 32: 377Google Scholar
  35. 35.
    Schreiber H (1989) Tumor immunology. In: Paul WE (ed) Fundamental immunology, 2nd edn. Raven, New York, pp 923–955Google Scholar
  36. 36.
    Siegel JP, Puri RK (1991) Interleukin-2 toxicity. J Clin Oncol 9: 694Google Scholar
  37. 37.
    Talmadge JE (1988) Therapeutic potential of cytokines: a comparison of preclinical and clinical studies. Prog Exp Tumor Res 32: 154Google Scholar
  38. 38.
    Wadler S, Schwartz EL (1990) Antineoplastic activity of combination of interferon and cytotoxic agents against experimental and human malignancies: a review. Cancer Res 50: 3473Google Scholar
  39. 39.
    Wiltrout RH, Salup RR (1988) Adoptive immunotherapy in combination with chemotherapy for cancer treatment. Prog Exp Tumor Res 32: 128Google Scholar
  40. 40.
    Yoneda K, Yamamoto T, Osaki T (1989) Influence of interferon on adriamycin uptake of cultured tumor cells. Int J Cancer 44: 483Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Eli Kedar
    • 1
  • Yaron Rutkowski
    • 1
  • Benny Leshem
    • 1
  1. 1.The Lautenberg Center for General and Tumor ImmunologyThe Hebrew University — Hadassah Medical SchoolJerusalemIsrael

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