Skip to main content
PMC home page
Cancer Immunology, Immunotherapy : CII logoLink to Cancer Immunology, Immunotherapy : CII
. 1992 Jan;35(1):63–68. doi: 10.1007/BF01741057

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 1,✉, Yaron Rutkowski 1, Benny Leshem 1
PMCID: PMC11038410  PMID: 1611625

Abstract

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

References

  • 1.Asher AL, Mulé JJ, Kasid A, Restifo NP, Salo JC, Reichert CM, Jaffe G, Fendly B, Kriegler M, Rosenberg SA. 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. 1991;146:3227. [PMC free article] [PubMed] [Google Scholar]
  • 2.Atzpodien J, Körfer A, Franks CR, Poliwoda H, Kirchner H. Home therapy with recombinant interleukin-2 and interferon-α2b in advanced human malignancies. Lancet. 1990;335:1509. doi: 10.1016/0140-6736(90)93039-r. [DOI] [PubMed] [Google Scholar]
  • 3.Balkwill FR. Interferons. Lancet. 1989;1:1060. doi: 10.1016/s0140-6736(89)92455-0. [DOI] [PubMed] [Google Scholar]
  • 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. Laboratory correlates of adoptive immunotherapy with recombinant interleukin-2 and lymphokine-activated killer cells in humans. Cancer Res. 1988;48:4409. [PubMed] [Google Scholar]
  • 5.Borden EC. Augmented tumor-associated antigen expression by interferons. J Natl Cancer Inst. 1988;80:148. doi: 10.1093/jnci/80.3.148. [DOI] [PubMed] [Google Scholar]
  • 6.Borden EC, Sidky YA, Hatcher JF, Bryan GT. Schedule-dependent variations in the response of murine P388 leukemia to cyclophosphamide in combination with interferons-α/β. Cancer Res. 1988;48:2329. [PubMed] [Google Scholar]
  • 7.Brunda MJ, Bellantoni D, Sulich V. 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. 1987;40:365. doi: 10.1002/ijc.2910400314. [DOI] [PubMed] [Google Scholar]
  • 8.Cameron RB, McIntosh JK, Rosenberg SA. 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. 1988;48:5810. [PubMed] [Google Scholar]
  • 9.Dillman RO, Oldham RK, Tauer KW, Orr DW, Barth NM, Blumenschein G, Arnold J, Birch R, West WH. Continuous interleukin-2 and lymphokine-activated killer cells for advanced cancer: a national biotherapy study group trial. J Clin Oncol. 1991;9:1233. doi: 10.1200/JCO.1991.9.7.1233. [DOI] [PubMed] [Google Scholar]
  • 10.Elias L, Crissman HA. Interferon effects upon the adenocarcinoma 38 and HL-60 cell lines: antiproliferative responses and synergistic interactions with halogenated pyrimidine antimetabolites. Cancer Res. 1988;48:4868. [PubMed] [Google Scholar]
  • 11.Faltynek CR, Oppenheim JJ. Interferons in host defense. J Natl Cancer Inst. 1988;80:151. doi: 10.1093/jnci/80.3.151. [DOI] [PubMed] [Google Scholar]
  • 12.Foon KA. Biological response modifiers: the new immunotherapy. Cancer Res. 1989;49:1621. [PubMed] [Google Scholar]
  • 13.Ghosh AK, Dazzi H, Thatcher N, Moore M. 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. 1989;43:410. doi: 10.1002/ijc.2910430311. [DOI] [PubMed] [Google Scholar]
  • 14.Greenberg PD. Adoptive T cell therapy of tumors: Mechanisms operative in the recognition and elimination of tumor cells. Adv Immunol. 1991;49:281. doi: 10.1016/s0065-2776(08)60778-6. [DOI] [PubMed] [Google Scholar]
  • 15.Hamblin TJ, Davies B, Sadullah S, Oskam R, Palmer P, Franks CR. 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. 1991;10:294. [Google Scholar]
  • 16.Hirsh M, Lipton A, Harvey H, Givant E, Hopper K, Jones G, Zeffren J, Levitt D. Phase I study of interleukin-2 and interferon alpha-2a as outpatient therapy for patients with advanced malignancy. J Clin Oncol. 1990;8:1657. doi: 10.1200/JCO.1990.8.10.1657. [DOI] [PubMed] [Google Scholar]
  • 17.Hosokawa M, Sawamura Y, Morikage T, Okada F, Xu ZY, Morikawa K, Itoh K, Kobayashi H. 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. 1988;26:250. doi: 10.1007/BF00199937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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) [DOI] [PubMed]
  • 19.Kedar E, Klein E (1992) Cancer immunotherapy: are the results discouraging? Can they be improved? Adv Cancer Res (in press) [DOI] [PubMed]
  • 20.Kedar E, Ben-Aziz R, Shiloni E. 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. 1988;24:494. [PubMed] [Google Scholar]
  • 21.Kedar E, Ben-Aziz R, Epstein E, Leshem B. 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. 1989;29:74. doi: 10.1007/BF00199920. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 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. Cytokines increase the therapeutic efficacy of cancer chemotherapy and facilitate reconstitution following bone marrow transplantation. In: Adam A, Rubinstein E, editors. Recent advances in chemotherapy. Bat-Yam: Lewin-Epstein; 1990. pp. 840.1–840.8. [Google Scholar]
  • 23.Kinnon C, Levinsky RJ. Gene therapy for cancer. Eur J Cancer. 1990;26:638. doi: 10.1016/0277-5379(90)90096-c. [DOI] [PubMed] [Google Scholar]
  • 24.Krosnick JA, Mulè JJ, McIntosh JK, Rosenberg SA. Augmentation of antitumor efficacy by the combination of recombinant tumor necrosis factor and chemotherapeutic agents in vivo. Cancer Res. 1989;49:3729. [PubMed] [Google Scholar]
  • 25.Leshem B, Kedar E. 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. 1990;171:1057. doi: 10.1084/jem.171.4.1057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.MacDonald HR, Cerottini JC, Ryser JE, Maryanski JL, Taswell C, Widmer MB, Brunner KT. Quantitation and cloning of cytolytic T lymphocytes and their precursors. Immunol Rev. 1980;51:93. doi: 10.1111/j.1600-065x.1980.tb00318.x. [DOI] [PubMed] [Google Scholar]
  • 27.Mitchell MS. Combining chemotherapy with biological response modifiers in treatment of cancer. J Natl Cancer Inst. 1988;80:1445. doi: 10.1093/jnci/80.18.1445. [DOI] [PubMed] [Google Scholar]
  • 28.Parmiani G. An explanation of the variable clinical response to interleukin-2 and LAK cells. Immunol Today. 1990;11:113. doi: 10.1016/0167-5699(90)90046-c. [DOI] [PubMed] [Google Scholar]
  • 29.Richards JM, Priest E, Hamasaki V, Skosey P, Ramming K. Sequential chemoimmunotherapy for metastatic melanoma (abstract) Proc Am Soc Clin Oncol. 1991;10:298. doi: 10.1200/JCO.1992.10.8.1338. [DOI] [PubMed] [Google Scholar]
  • 30.Rosenberg SA, Longo DL, Lotze MT. Principles and applications of biologic therapy. In: DeVita VT, Hellman S, Rosenberg SA, editors. Cancer. Principles and practice of oncology. 3rd edn. Philadelphia: Lippincott; 1989. pp. 301–347. [Google Scholar]
  • 31.Rosenberg SA, Lotze MT, Yang JC, Aebersold PM, Linehan WM, Seipp CA, White DE. Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg. 1989;210:474. doi: 10.1097/00000658-198910000-00008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Rosenberg SA, Lotze MT, Yang JC, Linehan WM, Seipp CA, Calabro S, Karp SE, Sherry RM, Steinberg S, White DE. Combination therapy with interleukin-2 and alpha-interferon for the treatment of patients with advanced cancer. J Clin Oncol. 1989;7:1863. doi: 10.1200/JCO.1989.7.12.1863. [DOI] [PubMed] [Google Scholar]
  • 33.Russell SJ. Lymphokine gene therapy for cancer. Immunol Today. 1990;11:196. doi: 10.1016/0167-5699(90)90081-j. [DOI] [PubMed] [Google Scholar]
  • 34.Scala S, Murphy LD, Tortora G, Cho-Chung Y, Bates S. Effects of differentiating agents (DA) on P-glycoprotein (Pgp) expression in a multidrug resistant breast cancer cell line (abstract) Proc Am Assoc Cancer Res. 1991;32:377. [Google Scholar]
  • 35.Schreiber H. Tumor immunology. In: Paul WE, editor. Fundamental immunology. 2nd edn. New York: Raven; 1989. pp. 923–955. [Google Scholar]
  • 36.Siegel JP, Puri RK. Interleukin-2 toxicity. J Clin Oncol. 1991;9:694. doi: 10.1200/JCO.1991.9.4.694. [DOI] [PubMed] [Google Scholar]
  • 37.Talmadge JE. Therapeutic potential of cytokines: a comparison of preclinical and clinical studies. Prog Exp Tumor Res. 1988;32:154. doi: 10.1159/000414677. [DOI] [PubMed] [Google Scholar]
  • 38.Wadler S, Schwartz EL. Antineoplastic activity of combination of interferon and cytotoxic agents against experimental and human malignancies: a review. Cancer Res. 1990;50:3473. [PubMed] [Google Scholar]
  • 39.Wiltrout RH, Salup RR. Adoptive immunotherapy in combination with chemotherapy for cancer treatment. Prog Exp Tumor Res. 1988;32:128. doi: 10.1159/000414676. [DOI] [PubMed] [Google Scholar]
  • 40.Yoneda K, Yamamoto T, Osaki T. Influence of interferon on adriamycin uptake of cultured tumor cells. Int J Cancer. 1989;44:483. doi: 10.1002/ijc.2910440318. [DOI] [PubMed] [Google Scholar]

Articles from Cancer Immunology, Immunotherapy : CII are provided here courtesy of Springer

RESOURCES