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. 1989 Apr;28(4):275–281. doi: 10.1007/BF00205237

A phase-II study of low-dose cyclophosphamide and recombinant human interleukin-2 in metastatic renal cell carcinoma and malignant melanoma

Albrecht Lindemann 1, Klaus Höffken 2, Reinhold E Schmidt 3, Volker Diehl 4, Otto Kloke 2, Heinold Gamm 1, Jörg Hayungs 2, Wolfgang Oster 1, Markus Böhm 1, Jonathan E Kolitz 5, Chris R Franks 6, Friedhelm Herrmann 1, Roland H Mertelsmann 1,✉
PMCID: PMC11038640  PMID: 2784715

Abstract

Recent preclinical and clinical studies that have demonstrated antitumor activity of high-dose recombinant interleukin-2 (rIL-2), and animal models that demonstrated a synergistic effect of low-dose cyclophosphamide, led us to study rIL-2 (Cetus Corp., Emeryville, Calif) in a phase II clinical trial in combination with low-dose cyclophosphamide in 32 patients, 18 with malignant melanoma and 14 with renal cell carcinoma. rIL-2 was given once daily at 3×106 U/m2, as a 30-min infusion for 14 days in cycle I and for 2×5 days in cycles II and III respectively; if tolerated, the dose was increased to a maximum of 6×106 U m−2 day−1; the cycles, separated by 1 week treatment-free intervals, were preceded each by a single i.v. bolus of cyclophosphamide at 350 mg/m2. The most prominent side-effects encountered in this trial consisted of a capillary leak syndrome, myalgia and fever that required dose reduction during the first cycle in one-half of the patients. Given the limit of tolerable toxicities in a standard care unit, the regimen employed achieved minor antitumor activity. No remission was achieved in patients with renal cell carcinoma, and 15% of melanoma patients showed objective responses (partial response + minor response).

Keywords: Melanoma, Renal Cell Carcinoma, Antitumor Activity, Melanoma Patient, Metastatic Renal Cell Carcinoma

References

  • 1.Atkins MB, Gould JA, Allegretto M, Li JL, Dempsey RA, Rudders RA, Parkinson DR, Reichlin S, Mier JW. Phase I evaluation of recombinant interleukin-2 in patients with advanced malignant disease. J Clin Oncol. 1986;4:1380. doi: 10.1200/JCO.1986.4.9.1380. [DOI] [PubMed] [Google Scholar]
  • 2.Berd D, Mastrangelo MJ. Effect of low dose cyclophosphamide on the immune system of cancer patients: reduction of T suppressor function without depletion of the CD8+ subset. Cancer Res. 1987;47:3317. [PubMed] [Google Scholar]
  • 3.Berd D, Maguire HC, Mastrangelo MJ. Induction of cell mediated immunity of autologous melanoma cells and regression of metastases after treatment with melanoma cell vaccine preceded by cyclophosphamide. Cancer Res. 1987;46:2572. [PubMed] [Google Scholar]
  • 4.Beutler B, Cerami A. Cachectin: more than a tumor necrosis factor. N Engl J Med. 1987;316:379. doi: 10.1056/NEJM198702123160705. [DOI] [PubMed] [Google Scholar]
  • 5.Cheever MA, Greenberg PD, Fefer A. Specific adoptive therapy of established leukemia with syngeneic lymphocytes sequentially immunized in vivo and in vitro and non specifically expanded by culture with interleukin 2. J Immunol. 1981;126:1318. [PubMed] [Google Scholar]
  • 6.Cheever MA, Thompson JA, Peace DJ, Greenberg PD. Potential uses of interleukin 2 in cancer therapy. Immunobiology. 1987;172:365. doi: 10.1016/S0171-2985(86)80118-8. [DOI] [PubMed] [Google Scholar]
  • 7.Dinarello CA. Multiple biological properties of recombinant interleukin 1 (beta) Immunobiology. 1986;172:301. doi: 10.1016/S0171-2985(86)80112-7. [DOI] [PubMed] [Google Scholar]
  • 8.Ettinghausen SE, Lipford EH, III, Mule JJ, White DE, Platanias L, Young NS, Rosenberg SA. Systemic administration of recombinant interleukin 2 stimulates in vivo lymphoid cell proliferation in tissues. J Immunol. 1985;135:1488. [PubMed] [Google Scholar]
  • 9.Ettinghausen SE, Moore JG, White DE, Platanias L, Young NS, Rosenberg SA. Hematologic effects of immunotherapy with lymphokine-activated killer cells and recombinant interleukin-2 in cancer patients. Blood. 1987;69:1654. [PubMed] [Google Scholar]
  • 10.Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA. Lymphokine activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2 activated autologous human peripheral blood lymphocytes. J Exp Med. 1982;155:1823. doi: 10.1084/jem.155.6.1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Hefeneider SH, Conlon PJ, Henney CS, Gillis S. In vivo interleukin 2 administration augments the generation of alloreactive cytolytic T lymphocytes and resident natural killer cells. J Immunol. 1983;130:222. [PubMed] [Google Scholar]
  • 12.Herberman RB, Nunn ME, Holden HT, Lavrin DH. Natural cytotoxic reactivity to mouse lymphoid cells against syngeneic and allogenic tumors. II. Characterization of effector cells. Int J Cancer. 1975;16:230. doi: 10.1002/ijc.2910160205. [DOI] [PubMed] [Google Scholar]
  • 13.Herrmann F, Cannistra SA, Lindemann A, Mertelsmann RH, Rambaldi A, Griffin JD (1988) Functional consequences of monocyte interleukin-2 receptor expression: induction of monokines by interferon-gamma and interleukin-2. J Immunol (in press) [PubMed]
  • 14.Kolitz JE, Wong GY, Welte K, Merluzzi VJ, Engert A, Bialas T, Polivka A, Bradley EC, Konrad M, Gnecco C, Oettgen HF, Mertelsmann R (1988) Phase I trial of recombinant interleukin-2 and cyclophosphamide: augmentation of cellular immunity and T cell mitogenic response with long term administration of rIL-2. J Biol Response Mod (in press) [PubMed]
  • 15.Krigel R, Padavic-Shaller KA, Rudolph AR, Litwin S, Konrad M, Bradley EC, Comis RL. A phase I study of recombinant interleukin-2 (rIL-2) plus recombinant beta interferon. Cancer Res. 1987;48:3875. [PubMed] [Google Scholar]
  • 16.Lotze MT, Line BR, Mathisen DJ, Rosenberg SA. The in vivo distribution of autologous human and murine lymphoid cells grown in T cell growth factor (TCGF): implications for the adoptive immunotherapy of tumors. J Immunol. 1980;125:1487. [PubMed] [Google Scholar]
  • 17.Lotze MT, Grimm EA, Mazumder A, Strausser JL, Rosenberg SA. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T cell growth factor. Cancer Res. 1981;41:4420. [PubMed] [Google Scholar]
  • 18.Lotze MT, Frana LW, Sharrow SO, Robb RJ, Rosenberg SA. In vivo administration of human interleukin-2. I. Half life and immunologic effects of the Jurkat cell line-derived interleukin-2. J Immunol. 1985;134:157. [PubMed] [Google Scholar]
  • 19.Lotze MT, Matory YL, Ettinghausen SE, Rayner AA, Sharrow SO, Seipp CAY, Custer MC, Rosenberg SA. In vivo administration of purified human interleukin-2. II. Half life, immunologic effects, and expansion of peripheral lymphoid cells in vivo with recombinant interleukin-2. J Immunol. 1985;135:2865. [PubMed] [Google Scholar]
  • 20.Mitchell MM, Kempf RA, Harel W, Shau H, Boswell WD, Lind S, Bradley EC. Effectiveness and tolerability of low-dose cyclophosphamide and low-dose intravenous interleukin-2 in disseminated melanoma. J Clin Oncol. 1988;6:409. doi: 10.1200/JCO.1988.6.3.409. [DOI] [PubMed] [Google Scholar]
  • 21.Mule JJ, Shu S, Rosenberg SA. The anti-tumor efficacy of lymphokine activated killer cells and recombinant interleukin-2 in vivo. J Immunol. 1985;135:646. [PubMed] [Google Scholar]
  • 22.North RJ. Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor induced suppressor T cells. J Exp Med. 1982;55:1063. doi: 10.1084/jem.155.4.1063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Oster W, Lindemann A, Mertelsmann RH, Herrmann F (1988) Regulation of gene expression of M-, G-, GM-, and multi-CSF in normal and malignant hemopoietic cells. Blood cells (in press) [PubMed]
  • 24.Ozer H, Cowens JW, Colvin M, Nussbaum-Blumenson A, Sheedy D. In vitro effects of 4-hydroxyperoxycyclo-phosphamide on human immunoregulatory T subset function. J Exp Med. 1982;155:276. doi: 10.1084/jem.155.1.276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Phillips JH, Gemlo BT, Myers WW, Rayner AA, Lanier LL. In vivo and in vitro activation of natural killer cells in advanced cancer patients undergoing combined recombinant interleukin-2 and LAK cell therapy. J Clin Oncol. 1987;5:1933. doi: 10.1200/JCO.1987.5.12.1933. [DOI] [PubMed] [Google Scholar]
  • 26.Pui CH, IP SH, Kung P, Dodge RK, Berard CW, Christ WM, Murphy SB. High serum interleukin-2 receptor levels are related to advanced disease and a poor outcome in childhood Non-Hodgkin's lymphoma. Blood. 1987;70:624. [PubMed] [Google Scholar]
  • 27.Rayner AA, Grimm EA, Lotze MT, Chu EW, Rosenberg SA. Lymphokine-activated killer (LAK) cells. Analysis of factors relevant to the immunotherapy of human cancer. Cancer. 1987;55:1327. doi: 10.1002/1097-0142(19850315)55:6<1327::aid-cncr2820550628>3.0.co;2-o. [DOI] [PubMed] [Google Scholar]
  • 28.Rosenberg SA, Mule JJ, Spiess PJ, Reichert CM, Schwarz CL. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med. 1985;161:1169. doi: 10.1084/jem.161.5.1169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WM, Robertson CN, Lee RE, Rubin JT, Seipp CA, Simpson CG, White DE. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med. 1987;316:889. doi: 10.1056/NEJM198704093161501. [DOI] [PubMed] [Google Scholar]
  • 30.Silagi S, Schaefer AE. Successful immunotherapy of mouse melanoma and sarcoma with recombinant interleukin 2 and cyclophosphamide. J Biol Response Mod. 1986;5:411. [PubMed] [Google Scholar]
  • 31.Sondel PM, Kohler PC, Hank JA, Moore KH, Rosenthal NS, Sosman JA, Bechhofer R, Storer B. Clinical and immunological effects of recombinant interleukin 2 given by repetitive weekly cycles to patients with cancer. Cancer Res. 1988;48:2561. [PubMed] [Google Scholar]
  • 32.Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kino GC, Lowry SF, Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteriaemia. Nature. 1987;330:662. doi: 10.1038/330662a0. [DOI] [PubMed] [Google Scholar]
  • 33.Wagner DK, Kiwanuka J, Edwards BK, Rubin LA, Lelson DL, Magrath IT. Soluble interleukin-2 receptor levels in patients with undifferentiated and lymphoblastic lymphomas: correlation with survival. J Clin Oncol. 1987;5:1262. doi: 10.1200/JCO.1987.5.8.1262. [DOI] [PubMed] [Google Scholar]
  • 34.West WH, Tauer KW, Yanelli JR, Marshall GD, Orr DW, Thurman GB, Oldham RK. Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of cancer. N Engl J Med. 1987;316:898. doi: 10.1056/NEJM198704093161502. [DOI] [PubMed] [Google Scholar]
  • 35.Winkelhake JL, Stampfl S, Zimmerman RJ. Synergistic effects of combination therapy with human recombinant interleukin-2 and tumor necrosis factor in murine tumor models. Cancer Res. 1987;47:3948. [PubMed] [Google Scholar]
  • 36.Yokoto T, Coffman RL, Hayiwara H, Rennick DM, Takebe Y, Yokota K, Gemmell L, Shrader B, Yang G, Meyerson P, Luh J, Hoy P, Pene J, Briere F, Spits H, Branchereau J, DeVries J, Lee FD, Arai N, Arai K-I. Isolation and characterization of lymphokine cDNA clones encoding mouse and human IgA-enhancing factor and eosinophil colony-stimulating factor activities: relationship to interleukin 5. Proc Natl Acad Sci USA. 1987;84:7388. doi: 10.1073/pnas.84.21.7388. [DOI] [PMC free article] [PubMed] [Google Scholar]

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