Abstract
We describe here a mainly topical interleukin-2 (IL-2) application in pulmonary metastatic renal-cell carcinoma: a high-dose long-term inhalation of IL-2 (90% of IL-2 dose) and low-dose systemic subcutaneous IL-2 (10% of IL-2 dose) and systemic subcutaneous interferon α (IFN α). The effectiveness of this treatment is remarkable. No pulmonary metastases progressed during treatment. One complete response, 8 partial responses, and 6 cases of stable disease were achieved in the lungs of the 15 patients. In addition, 3 of 7 patients had partial responses and 1 of 7 had stabilization of non-pulmonary metastases. Overall response according to WHO criteria was 1 complete response, 6 partial responses, 2 mixed responses, 5 stable diseases and 1 progressive disease. Toxicity was low. Only WHO grade I toxicity occurred, except for a single grade II event (bronchospasm). This allowed long-term ambulatory treatment (1–23 months) inclusion of high-risk patients, and inclusion of patients with advanced disease. The expected mean survival of patients was 9.9 months, the actual mean survival is now 19.1 months, and 11 of 15 patients are still alive. Quality of life during treatment was good. Inhalation of IL-2 serves as a clinical model for high effectiveness and low toxicity of long-term local IL-2 application. We conclude that mainly local treatment might be the key to successful nontoxic use of IL-2 in cancer patients.
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Abrams J, Rayner A, Wiernik A, Parkinson D et al. (1989) High dose interleukin-2 without lymphokine activated killer cells. Inactive in advanced renal-cell cancer. Proc Am Assoc Cancer Res 30:A1507
Atzpodien J, Körfer A, Franks CR, Poliwoda H et al. (1990) Home therapy with recombinant interleukin-2 and interferon-α2b in advanced human malignancies. Lancet 335:1509
Aulitzky WE, Kessler M, Wilhelm M, Huland E et al. (1993) Aerosolized natural interleukin 2 for treatment of advanced malignancy: results of a phase I trial. Ann Hematol 66 [Suppl 2]:A109
Bartsch HH, Adler M, Ringert RH et al. (1990) Sequential therapy of recombinant interferon alpha (IFN-A) and recombinant interleukin-2 (IL-2) in patients with advanced renal-cell carcinoma (RCC). Proc Annu Meet Am Soc Clin Oncol 9:A556
Bubenik J, Perlmann P, Indrova M et al. (1983) Growth inhibition of an MC induced mouse sarcoma by TCGF (IL-2)-containing preparations. Cancer Immunol Immunother 14:205–206
Bukowski RM, Goodman P, Crawford ED et al. (1989) Phase II evaluation of recombinant interleukin-2 (RIL-2) in metastatic renal-cell carcinoma (RCC): SWOG 8617. Proc Annu Meet Am Soc Clin Oncol 8:A556
Elson PJ, Witte RS, Trump DL (1988) Prognostic factors for survival in patients with recurrent or metastatic renal-cell carcinoma. Cancer Res 48:7310–7313
Ettinghausen SE, Rosenberg SA (1986) Immunotherapy of murine sarcomas using lymphokine activated killer cells: optimization of the schedule and route of administration of recombinant interleukin-2. Cancer Res 46:1784–1792
Figlin R, Citron M, Whitehead R et al. (1990) Low dose continuous infusion recombinant human interleukin-2 (rhIL-2) and roferon; an active outpatient regimen for metastatic renal-cell carcinoma (RCCa). Proc Annu Meet Am Soc Clin Oncol 9:A553
Gering AJH, Thorpe R (1988) Immunological standardization. The international standard for human interleukin-2. Calibration by international collaborative study. J Immunol 114:3–9
Grimm EA, Mazumder A, Zhang HZ et al. (1982) Lymphokine-activated killer cell phenomenon: lysis of natural killer-resistant fresh solid tumor cells by interleukin-2-activated autologous peripheral blood lymphocytes. J Exp Med 155:1823–1841
Heinzer H, Huland E, Huland H (1992) Adverse reaction to contrast material in a patient treated with local interleukin-2. Am J Radiol 158:1407
Huland E, Huland H (1989) Local continuous high dose interleukin-2. A new therapeutic model for the treatment of advanced bladder carcinoma. Cancer Res 49:5469–5474
Huland E, Huland H, Heinzer H (1992) Interleukin-2 by inhalation: local therapy for metastatic renal cell carcinoma. J Urol 147:344–348
Lafreniere R, Rosenberg SA (1985 a) Successful immunotherapy of murine experimental hepaptic metastases with lymphokine-activated killer cells and recombinant interleukin 2. Cancer Res 45:3735–3741
Lafreniere R, Rosenberg SA (1985 b) Adoptive immunotherapy of murine hepatic metastases with lymphokine activated killer (LAK) cells and recombinant interleukin 2 (RIL 2) can mediate the regression of both immunogenic and nonimmunogenic sarcomas and an adenocarcinoma. J Immunol 135:4273–4280
Lindemann A, Monson JRT, Stahel RA et al. (1990) “Low-intensity” combination treatment with r-interleukin-2 (rh-IL-2) and r-interferon alfa-2a (rh-IFN-a-2a) in renal-cell carcinoma. A multicenter phase II trial. Proc Annu Meet Am Soc Clin Oncol 9:A584
Markowitz A, Talpaz M, Lee K et al. (1989) Phase I–II study of recombinant interleukin-2 (RIL-2) plus recombinant interferon-alpha 2a (FIFN-alpha) in renal-cell carcinoma (RCC). Proc Annu Meet Am Soc Clin Oncol 8:A568
Mittelman C, Puccio C, Ahmed T et al. (1990) Phase II trial of recombinant interleukin-2 (IL-2) and roferon A (IFN) in patients (PTS) with advanced renal-cell carcinoma. Proc Annu Meet Am Soc Clin Oncol 9:A736
Philip T, Stoter G, Jasmin C et al. (1989) Recombinant human interleukin-2 with or without LAK cells in metastatic renal-cell carcinoma. Proc Annu Meet Am Soc Clin Oncol 8:A507
Rosenberg SA, Lotze MT, Leitman S et al. (1985 a) Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 313:1485–1492
Rosenberg SA, Mulé JJ, Spiess PJ et al. (1985 b) Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin-2. J Exp Med 161:1169–1188
Rosenberg SA, Spiess P, Lafreniere R (1986) A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 233:1318–1321
Rosenberg SA, Lotze MT, Muul LM et al. (1987) 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 316:889–897
Rossio JL, Thurman GB, Long C et al. (1989) The BRMP IL-2 reference reagent. Lymphokine Res 5 [Suppl 1]:13
Sosman JA, Kohler PC, Hank J et al. (1988 a) Repetitive weekly cycles of recombinant human interleukin-2: responses of renal carcinoma with acceptable toxicity. J Natl Cancer Inst 80:60
Sosman JA, Kohler PC, Hank J et al. (1988 b) Repetitive weekly cycles of interleukin-2. II. Clinical and immunologic effects of dose, schedule, and addition of indomethacin. J Natl Cancer Inst 80:1451
Voss SD, Weil-Hillman G, Hank JA et al. (1989) The clinical immunobiology of interleukin-2: potential modified uses for improved cancer treatment. Bull NY Acad Med 65:93–110
Wang J, Walle A, Gordon B et al. (1987) Adoptive immunotherapy for stage IV renal-cell carcinoma. A novel protocol utilizing periodate and interleukin-2-activated autologous leukocytes and continuous infusions of low-dose interleukin-2. Am J Med 83:1016–1023
West WH, Tauer KW, Yannli JR et al. (1987) Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med 316:898–905
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Huland, E., Heinzer, H. & Huland, H. Inhaled interleukin-2 in combination with low-dose systemic interleukin-2 and interferon α in patients with pulmonary metastatic renal-cell carcinoma: effectiveness and toxicity of mainly local treatment. J Cancer Res Clin Oncol 120, 221–228 (1994). https://doi.org/10.1007/BF01372560
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DOI: https://doi.org/10.1007/BF01372560