Background: Interleukin-2 (IL-2) is a cytokine produced by activated T cells, which has shown powerful immunostimulatory and antineoplastic properties. Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated cancer with abundant lymphocyte infiltration histologically. The activity of IL-2 in the treatment of NPC patients is currently unknown. A phase II study was, therefore, initiated to evaluate the efficacy, toxicity and immunological consequences of intravenous bolus IL-2 in patients with recurrent/metastatic NPC. Methods: Between November 1996 and April 1997, 14 patients with recurrent/metastatic NPC were entered into the study. Recombinant IL-2 (Proleukin, Chiron) was injected by intravenous bolus every 8 h at 72,000 IU/kg for a maximum of 15 doses. After 7 days, patients were retreated with a second identical cycle of therapy. Those patients who were stable or responding to treatment 5–6 weeks later went on to receive another course (two cycles) of therapy. All patients received prophylactic antibiotics and antipyretic medicine. Response and toxicities were evaluated. Serial plasma level of TNF-α, IL-6, soluble IL-2 receptor, IL-10 and soluble CD8 were determined. Results: Fourteen patients received a total of 34 cycles of therapy. No response was observed. Fifty percent had stable disease, 50% had progressive disease after a median of two cycles of therapy. There was one treatment-related death from acute myocardial infarction. Body weight increase (>5%) occurred in 80% of cycles, and hypotension (BP <80 mm Hg systolic) occurred in 53%. Serum creatinine increase (>2 mg%) occurred in 24% of cycles, and SGOT/SGPT increase (>3×) in 10% of cycles. Symptoms of somnolence, general malaise, nausea and vomiting, pruritus, xerostomia, desquamation were generally mild to moderate but rapidly reversible. Conclusion: The single modality of intravenous bolus IL-2 at the dose level of 72,000 IU/kg is clinically ineffective in NPC patients. Potential mechanisms of the ineffectiveness of IL-2 therapy on NPC patients are discussed.

1.
Zeng Y: Seroepidemiological studies on nasopharyngeal carcinoma in China. Adv Cancer Res 1985;44:121–138.
2.
Niedobitek G, Young LS, Sam CK, Brooks L, Prasad U, Rickinson AB: Expression of Epstein-Barr virus genes and of lymphocyte activation molecules in undifferentiated nasopharyngeal carcinoma. Am J Pathol 1992;140:879–887.
3.
Ferradini L, Miescher S, Stoeck M, Busson P, Barras C, Cerf-Bensussan N, Lipinski M, von Fliedner V, Tursz T: Cytotoxic potential despite impaired activation pathways in T lymphocytes infiltrating nasopharyngeal carcinoma. Int J Cancer 1991;47:362–370.
4.
Lakhdar M, Ben Aribia MH, Maalej M, Ladgham A: Selective homing of phenotypically lytic cells within nasopharyngeal carcinoma biopsies: Numerous CD8- and CD16-positive cells in the tumor. Int J Cancer 1991;48:57–61.
5.
Busson P, Ganem G, Flores P, Mugneret F, Clausse B, Caillou B, Braham K, Wakasugi H, Lipinski M, Tursz T: Establishment and characterization of three transplantable EBV-containing nasopharyngeal carcinomas. Int J Cancer 1988;42:599–606.
6.
Morgan DA, Ruscetti FW, Gallo R: Selective in vitro growth of T lymphocytes from normal human bone marrows. Science 1976;193:1007–1008.
7.
Rosenberg SA, Lotze MT, Yang JC, Topalian SL, Chang AE, Schwartzentruber DJ, Aebersold P, Leitman S, Seipp CA: Prospective randomized trial of high-dose interleukin-2 alone or in conjuction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. J Natl Cancer Inst 1993;85:622–632.
8.
Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, Linehan WM, Robertson CN, Lee RE, Rubin JT: A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cell and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 1987;316:889–897.
9.
Yang JC, Topalian SL, Parkinson D, Schwartzentruber DJ, Weber JS, Ettinghausen SE, White DE, Steinberg SM, Cole DJ, Kim HI: Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: An interim report. J Clin Oncol 1994;12:1572–1576.
10.
Gehan EA: The determination of the number of patients required in a preliminary and follow-up trial of a new chemotherapeutic agent. J Chronic Dis 1961;13:346–353.
11.
Kruit WH, Bolhuis RL, Goey SH, Goey SH, Jansen RL, Eggermont AM, Batchelor D, Schmitz PI, Stoter G: Interleukin-2-induced thyroid dysfunction is correlated with treatment duration but not with tumor response. J Clin Oncol 1993;11:921–924.
12.
Karp SE: Low dose intravenous bolus interleukin-2 with interferon-alpha therapy for metastatic melanoma and renal cell carcinoma. J Immunother 1998;21:56–61.
13.
Rosenstein M, Ettinghausen SE, Rosenberg SA: Extravasation of intravascular fluid mediated by the systemic administration of recombinant interleukin-2. J Immunol 1986;137:1735–1742.
14.
Caligiuri MA, Murray C, Robertson MJ, Wang E, Cochran K, Cameron C, Schow P, Ross ME, Klumpp TR, Soiffer RJ: Selective modulation of human natural killer cells in vivo after prolonged infusion of low dose recombinant interleukin-2. J Clin Invest 1993;91:123–132.
15.
Lindemann A, Brossart P, Hoffken K, Flasshove M, Voliotis D, Diehl V, Kulmburg P, Wagner H, Mertelsmann R: Serum cytokine levels in cancer patients treated with different schedules of ultra-low-dose interleukin-2. J Immunother 1994;15:225–230.
16.
Gemlo BT, Palladino MAJ, Jaffe HS, Espevik TP, Rayner AA: Circulating cytokines in patients with metastatic cancer treated with recombinant interleukin-2 and lymphokine-activated killer cell. Cancer Res 1988;48:5864–5867.
17.
Mier JW, Vachino G, van der Meer JW, Numerof RP, Adams S, Cannon JG, Bernheim HA, Atkins MB, Parkinson DR, Dinarello CA: Induction of circulating tumor necrosis factor (TNF alpha) as the mechanism for the febrile response to interleukin-2 (IL-2) in cancer patients. J Clin Immunol 1988;8:426–436.
18.
von Rohr A, Ghosh AK, Thatcher N, Stern PL: Immunomodulation during prolonged treatment with combined interleukin-2 and interferon-alpha in patients with advanced malignancy. Br J Cancer 1993;67:163–171.
19.
Deehan DJ, Heys SD, Simpson WG, Broom J, Franks C, Eremin O: In vivo cytokine production and recombinant interleukin 2 immunotherapy: An insight into the possible mechanisms underlying clinical responses. Br J Cancer 1994;69:1130–1135.
20.
Akuffo H, Alexis A, Eidsmo L, Saed A, Nylen S, Maasho K: Natural killer cells in cross-regulation of IL-12 by IL-10 in Leishmania antigen-stimulated blood donor cells. Clin Exp Immunol 1999;117:529–534.
21.
Platzer C, Docke W, Volk H, Prosch S: Catecholamines trigger IL-10 release in acute systemic stress reaction by direct stimulation of its promoter/enhancer activity in monocytic cells. J Neuroimmunol 2000;105:31–38.
22.
Engelhardt M, Brennscheidt U, Mertelsmann R, Lindemann A: Interleukin-10 and phenomena of tolerance in interleukin-2 therapy (letter). J Clin Oncol 1996;14:1405–1406.
23.
Lissoni P, Brivio F, Viviani S, Fumagalli L: Which immunological parameters are clinically essential to monitor IL-2 cancer immunotherapy? J Biol Regul Homeost Agents 1999;13:110–114.
24.
Martens A, Janssen RA, Sleijfer DT, Heijn AA, Mulder NH, The TH, de Leij L: Early sCD8 plasma levels during subcutaneous rIl-2 therapy in patients with renal cell carcinoma correlate with response. Br J Cancer 1993;67:1118–1121.
25.
Kondo N, Kondo S, Shimizu A, Honjo T, Hamuro J: A soluble ‘anchorminus’ interleukin 2 receptor suppresses in vitro interleukin 2-mediated immune response. Immunol Lett 1988;19:299–307.
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