Abstract
Lymphocytosis is a marker of subcutaneous interleukin (IL)-2 therapy efficacy, whereas baseline elevated inflammatory indices were noticed in IL-2-resistant disease. The aim of this study was to analyse the relationship between pretreatment circulating values of IL-6, neopterin, sIL-2R, ESR and the changes in lymphocyte number in response to IL-2 administration. Twenty metastatic renal cell cancer patients were treated with subcutaneous IL-2 immunotherapy (6 000 000 IU day−1 for 6 days per week for 4 weeks); tumour response consisted of partial response (PR) in four patients, stable disease (SD) in eight patients and progressive disease (PD) in eight patients. Abnormally high pretreatment values of each marker were found as follows: IL-6 in seven patients, neopterin in nine patients, sIL-2R in 13 patients. In response to IL-2 immunotherapy, a significantly higher mean increase in lymphocyte number and a higher percentage of patients with tumour response or stable disease were observed when pretreatment values of IL-6, neopterin and sIL-2R were within the normal range, in comparison to patients with high values for these markers. The pretreatment excess of these serum inflammatory markers seems to negatively influence both the host and tumour response to IL-2 administration, by preventing the IL-2-induced lymphocytosis and resulting in tumour progression. Further studies are requested to verify if overall survival and quality of life may depend on pretreatment host immune status and/or lymphocyte response after IL-2 administration. © 1999 Cancer Research Campaign
Keywords: IL-2, immunotherapy, IL-6, neopterin, sIL-2R, lymphocytosis
Full Text
The Full Text of this article is available as a PDF (81.6 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Blay J. Y., Negrier S., Combaret V., Attali S., Goillot E., Merrouche Y., Mercatello A., Ravault A., Tourani J. M., Moskovtchenko J. F. Serum level of interleukin 6 as a prognosis factor in metastatic renal cell carcinoma. Cancer Res. 1992 Jun 15;52(12):3317–3322. [PubMed] [Google Scholar]
- Buzio C., De Palma G., Passalacqua R., Potenzoni D., Ferrozzi F., Cattabiani M. A., Manenti L., Borghetti A. Effectiveness of very low doses of immunotherapy in advanced renal cell cancer. Br J Cancer. 1997;76(4):541–544. doi: 10.1038/bjc.1997.422. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chouaib S., Fradelizi D. The mechanism of inhibition of human IL 2 production. J Immunol. 1982 Dec;129(6):2463–2468. [PubMed] [Google Scholar]
- Diamondstone L. S., Tollerud D. J., Fuchs D., Wachter H., Brown L. M., Maloney E., Kurman C. C., Nelson D. L., Blattner W. A. Factors influencing serum neopterin and beta 2-microglobulin levels in a healthy diverse population. J Clin Immunol. 1994 Nov;14(6):368–374. doi: 10.1007/BF01546321. [DOI] [PubMed] [Google Scholar]
- Figlin R., Gitlitz B., Franklin J., Dorey F., Moldawer N., Rausch J., deKernion J., Belldegrun A. Interleukin-2-based immunotherapy for the treatment of metastatic renal cell carcinoma: an analysis of 203 consecutively treated patients. Cancer J Sci Am. 1997 Dec;3 (Suppl 1):S92–S97. [PubMed] [Google Scholar]
- Fischer J. R., Schindel M., Stein N., Lahm H., Gallati H., Krammer P. H., Drings P. Selective suppression of cytokine secretion in patients with small-cell lung cancer. Ann Oncol. 1995 Nov;6(9):921–926. doi: 10.1093/oxfordjournals.annonc.a059360. [DOI] [PubMed] [Google Scholar]
- Gastl G. A., Abrams J. S., Nanus D. M., Oosterkamp R., Silver J., Liu F., Chen M., Albino A. P., Bander N. H. Interleukin-10 production by human carcinoma cell lines and its relationship to interleukin-6 expression. Int J Cancer. 1993 Aug 19;55(1):96–101. doi: 10.1002/ijc.2910550118. [DOI] [PubMed] [Google Scholar]
- Gooding R., Riches P., Dadian G., Moore J., Gore M. Increased soluble interleukin-2 receptor concentration in plasma predicts a decreased cellular response to IL-2. Br J Cancer. 1995 Aug;72(2):452–455. doi: 10.1038/bjc.1995.354. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Grimm E. A., Mazumder A., Zhang H. Z., Rosenberg S. A. 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 Jun 1;155(6):1823–1841. doi: 10.1084/jem.155.6.1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Göhring B., Riemann D., Rebmann U., Heynemann H., Schabel J., Langner J. Prognostic value of the immunomonitoring of patients with renal cell carcinoma under therapy with IL-2/IFN-alpha-2 in combination with 5-FU. Urol Res. 1996;24(5):297–303. doi: 10.1007/BF00304780. [DOI] [PubMed] [Google Scholar]
- Jeal W., Goa K. L. Aldesleukin (recombinant interleukin-2): a review of its pharmacological properties, clinical efficacy and tolerability in patients with renal cell carcinoma. BioDrugs. 1997 Apr;7(4):285–317. doi: 10.2165/00063030-199707040-00005. [DOI] [PubMed] [Google Scholar]
- Katsumata N., Eguchi K., Fukuda M., Yamamoto N., Ohe Y., Oshita F., Tamura T., Shinkai T., Saijo N. Serum levels of cytokines in patients with untreated primary lung cancer. Clin Cancer Res. 1996 Mar;2(3):553–559. [PubMed] [Google Scholar]
- Kim U. S., Papatestas A. E., Aufses A. H., Jr Prognostic significance of peripheral lymphocyte counts and carcinoembryonic antigens in colorectal carcinoma. J Surg Oncol. 1976;8(3):257–262. doi: 10.1002/jso.2930080312. [DOI] [PubMed] [Google Scholar]
- Kishimoto T. The biology of interleukin-6. Blood. 1989 Jul;74(1):1–10. [PubMed] [Google Scholar]
- Koo A. S., Armstrong C., Bochner B., Shimabukuro T., Tso C. L., deKernion J. B., Belldegrum A. Interleukin-6 and renal cell cancer: production, regulation, and growth effects. Cancer Immunol Immunother. 1992;35(2):97–105. doi: 10.1007/BF01741856. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lissoni P., Brivio F., Fumagalli L., Galimberti C., Cataldo M., Marsili M. T., Brivio O., Barni S., Tancini G., Angelini A. A study of interactions among markers of macrophage functions in metastatic solid tumors: neopterin levels in relation to those of tumor necrosis factor-alpha and of soluble interleukin-2 receptors. J Biol Regul Homeost Agents. 1994 Jan-Mar;8(1):32–35. [PubMed] [Google Scholar]
- Lissoni P., Viviani S., Santoro A., Barni S., Tancini G. Serum levels of interleukin-2 in cancer patients: preliminary considerations. Int J Biol Markers. 1989 Oct-Dec;4(4):203–206. doi: 10.1177/172460088900400404. [DOI] [PubMed] [Google Scholar]
- Lopez Hänninen E., Kirchner H., Atzpodien J. Interleukin-2 based home therapy of metastatic renal cell carcinoma: risks and benefits in 215 consecutive single institution patients. J Urol. 1996 Jan;155(1):19–25. [PubMed] [Google Scholar]
- Maltoni M., Pirovano M., Nanni O., Marinari M., Indelli M., Gramazio A., Terzoli E., Luzzani M., De Marinis F., Caraceni A. Biological indices predictive of survival in 519 Italian terminally ill cancer patients. Italian Multicenter Study Group on Palliative Care. J Pain Symptom Manage. 1997 Jan;13(1):1–9. doi: 10.1016/s0885-3924(96)00265-5. [DOI] [PubMed] [Google Scholar]
- Monson J. R., Ramsden C., Guillou P. J. Decreased interleukin-2 production in patients with gastrointestinal cancer. Br J Surg. 1986 Jun;73(6):483–486. doi: 10.1002/bjs.1800730620. [DOI] [PubMed] [Google Scholar]
- Palmer P. A., Atzpodien J., Philip T., Negrier S., Kirchner H., Von der Maase H., Geertsen P., Evers P., Loriaux E., Oskam R. A comparison of 2 modes of administration of recombinant interleukin-2: continuous intravenous infusion alone versus subcutaneous administration plus interferon alpha in patients with advanced renal cell carcinoma. Cancer Biother. 1993 Summer;8(2):123–136. doi: 10.1089/cbr.1993.8.123. [DOI] [PubMed] [Google Scholar]
- Palmer P. A., Vinke J., Philip T., Negrier S., Atzpodien J., Kirchner H., Oskam R., Franks C. R. Prognostic factors for survival in patients with advanced renal cell carcinoma treated with recombinant interleukin-2. Ann Oncol. 1992 Jun;3(6):475–480. doi: 10.1093/oxfordjournals.annonc.a058239. [DOI] [PubMed] [Google Scholar]
- Riesco A. Five-year cancer cure: relation to total amount of peripheral lymphocytes and neutrophils. Cancer. 1970 Jan;25(1):135–140. doi: 10.1002/1097-0142(197001)25:1<135::aid-cncr2820250120>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]
- Rubin L. A., Jay G., Nelson D. L. The released interleukin 2 receptor binds interleukin 2 efficiently. J Immunol. 1986 Dec 15;137(12):3841–3844. [PubMed] [Google Scholar]
- Rubin L. A., Kurman C. C., Fritz M. E., Biddison W. E., Boutin B., Yarchoan R., Nelson D. L. Soluble interleukin 2 receptors are released from activated human lymphoid cells in vitro. J Immunol. 1985 Nov;135(5):3172–3177. [PubMed] [Google Scholar]
- Scheid C., Young R., McDermott R., Fitzsimmons L., Scarffe J. H., Stern P. L. Immune function of patients receiving recombinant human interleukin-6 (IL-6) in a phase I clinical study: induction of C-reactive protein and IgE and inhibition of natural killer and lymphokine-activated killer cell activity. Cancer Immunol Immunother. 1994 Feb;38(2):119–126. doi: 10.1007/BF01526207. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schoof D. D., Terashima Y., Batter S., Douville L., Richie J. P., Eberlein T. J. Survival characteristics of metastatic renal cell carcinoma patients treated with lymphokine-activated killer cells plus interleukin-2. Urology. 1993 Jun;41(6):534–539. doi: 10.1016/0090-4295(93)90100-o. [DOI] [PubMed] [Google Scholar]
- Scott H. R., McMillan D. C., Crilly A., McArdle C. S., Milroy R. The relationship between weight loss and interleukin 6 in non-small-cell lung cancer. Br J Cancer. 1996 Jun;73(12):1560–1562. doi: 10.1038/bjc.1996.294. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sedlmayr P., Rabinowich H., Elder E. M., Ernstoff M. S., Kirkwood J. M., Herberman R. B., Whiteside T. L. Depressed ability of patients with melanoma or renal cell carcinoma to generate adherent lymphokine-activated killer cells. J Immunother (1991) 1991 Oct;10(5):336–346. doi: 10.1097/00002371-199110000-00005. [DOI] [PubMed] [Google Scholar]
- Stanley K. E. Prognostic factors for survival in patients with inoperable lung cancer. J Natl Cancer Inst. 1980 Jul;65(1):25–32. [PubMed] [Google Scholar]
- Tanner J., Tosato G. Impairment of natural killer functions by interleukin 6 increases lymphoblastoid cell tumorigenicity in athymic mice. J Clin Invest. 1991 Jul;88(1):239–247. doi: 10.1172/JCI115283. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tartour E., Dorval T., Mosseri V., Deneux L., Mathiot C., Brailly H., Montero F., Joyeux I., Pouillart P., Fridman W. H. Serum interleukin 6 and C-reactive protein levels correlate with resistance to IL-2 therapy and poor survival in melanoma patients. Br J Cancer. 1994 May;69(5):911–913. doi: 10.1038/bjc.1994.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Walther M. M., Johnson B., Culley D., Shah R., Weber J., Venzon D., Yang J. C., Linehan W. M., Rosenberg S. A. Serum interleukin-6 levels in metastatic renal cell carcinoma before treatment with interleukin-2 correlates with paraneoplastic syndromes but not patient survival. J Urol. 1998 Mar;159(3):718–722. [PubMed] [Google Scholar]
- Wojtowicz-Praga S. Reversal of tumor-induced immunosuppression: a new approach to cancer therapy. J Immunother. 1997 May;20(3):165–177. [PubMed] [Google Scholar]
- Yoshino I., Yano T., Murata M., Ishida T., Sugimachi K., Kimura G., Nomoto K. Tumor-reactive T-cells accumulate in lung cancer tissues but fail to respond due to tumor cell-derived factor. Cancer Res. 1992 Feb 15;52(4):775–781. [PubMed] [Google Scholar]
- Zorn U., Dallmann I., Grosse J., Kirchner H., Poliwoda H., Atzpodien J. Soluble interleukin 2 receptors abrogate IL-2 induced activation of peripheral mononuclear cells. Cytokine. 1994 Jul;6(4):358–364. doi: 10.1016/1043-4666(94)90058-2. [DOI] [PubMed] [Google Scholar]