Abstract
The Cytokine Working Group (CWG) was initially established in 1986 as the Extramural IL-2/LAK Working Group. With funding from the National Cancer Institute (NCI), the CWG was mandated to confirming data regarding the efficacy of the high-dose interleukin-2 (IL2)/lymphokine-activated killer cell (LAK cell) regimen piloted at the NCI in the treatment of renal cell cancer. Since those initial studies, the CWG has conducted a series of clinical trials, often with correlative immunologic investigations, to evaluate combination immunotherapy in attempts to enhance the efficacy of IL-2 or to reduce toxicity. Subsequently, the CWG conducted trials to demonstrate the activity of lower-dose outpatient combination cytokine regimens to help determine their role in the armamentarium of treatment for metastatic renal cell cancer. This has culminated in a phase III randomized trial comparing the activity of high-dose IL-2 with the activity of outpatient IL-2 plus interferon-α. The CWG also has honed the management of both high-dose IL-2 and outpatient IL-2 regimens to make these safer in the hands of experienced clinicians. In addition, the CWG has produced a series of carefully conducted clinical trials of new cytokines, again attempting to define their clinical efficacy as anticancer agents. These include studies of IL-4, IL-6, and IL-12. Currently, the CWG is conducting studies with new approaches to IL-2 therapy, as well as planning trials with new agents for treatment of renal cell cancer. This review describes these efforts conducted over the past 15 yr.
Similar content being viewed by others
References
Margolin, K.A., Rayner, A.A., Hawkins, M.J., Atkins, M.B., Dutcher, J.P., Fisher, R.J., et al. (1989). Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: analysis of toxicity and management guidelines. J. Clin. Oncol. 7:486–498.
Gaynor, E., Vitek, L., Sticklin, L., Creekmore, S.P., Ferraro, M.E., Thomas, J.X., Jr., et al. (1988). The hemodynamic effects of treatment with interleukin-2 and lymphokine-activated killer cells. Ann. Intern. Med. 109:953–958.
Lee, R.I., Lotze, M.T., Skibber, J.M., Tucker, E., Bonow, R.O., Ognibene, F.P., et al. (1989). Cardiorespiratory effects of immunotherapy with interleukin-2. J. Clin. Oncol. 7:7–20.
Vogelzang, P.J., Bloom, S., Mier, J. and Atkins, M.B. (1992). Chest roentgenographic abnormalities in interleukin-2 recipients: incidence and correlation with clinical parameters. Chest 101:746–752.
Shalmi, C., Dutcher, J.P., Feinfeld, D.A., Chun, K.J., Saleemi, K.R., Freeman, L.M., et al. (1990). Acute renal dysfunction during interleukin-2 treatment: suggestion of an intrinsic renal lesion. J. Clin. Oncol. 8:1839–1846.
Oleksowicz, L., Strack, M., Dutcher, J.P., Sussman, I., Caliendo, G., Sparano, J., et al. (1994). PII. A distinct coagulopathy associated with interleukin-2 therapy. Br. J. Haematol. 88:892–894.
Oleksowicz, L., Zuckerman, D., Mrowiec, Z., Puszkin, E. and Dutcher, J.P. (1994). Effects of interleukin-2 administration on platelet function in cancer patients. Am. J. Hematol. 45:224–231.
Klemper, M.S., Noring, R., Mier, J.W. and Atkins, M.B. (1990). An acquired chemotactic defect in neutrophils from patients receiving interleukin-2 immunotherapy. N. Engl. J. Med. 322:959–965.
Atkins, M.B., Mier, J.W., Parkinson, D.R., Gould, J.A., Berkman, E.M. and Kaplan, M.M. (1988). Hypothyroidism after treatment with interleukin-2 and lymphokine-activated killer cells. N. Engl. J. Med. 318:1557–1563.
Weijl, N.I., van der Harst, D., Brand, A., Kooy, Y., van Luxemburg, S., Schroder, J., et al. (1993). Hypothyroidism during immunotherapy with interleukin-2 is associated with antithyroid antibodies and response to treatment. J. Clin. Oncol. 11:376–383.
Howard, M., Farrar, J., Hilfiker, M., Johnson, B., Takatsu, K., Hamaoka, T., et al. (1982). Identification of a T-cell-derived B cell growth factor distinct from interleukin-2. J. Exp. Med. 155:914–919.
Paul, W.E. (1984). Nomenclature of lymphokines which regulate B-lymphocytes. Mol. Immunol. 21:343–349.
Kawakami, Y., Rosenberg, S.A. and Lotze, M.T. (1988). Interleukin-4 promotes the growth of tumor-infiltrating lymphocytes cytotoxic for human autologous melanoma. J. Exp. Med. 168:2183–2191.
Hoon, D.S.B., Okun, E., Banez, M., Irie, R.F. and Morton, D.L. (1991). Interleukin-4 alone and with gamma-interferon or tumor necrosis factor inhibits cell growth and modulates cell surface antigens on human renal cell carcinomas. Cancer Res. 51:5687–5693.
Bosco, M., Giovarelli, M., Forni, M., Modesti, A., Scarpa, S., Masuelli, L., et al. (1990). doses of IL-4 injected perilymphatically in tumor-bearing mice inhibit the growth of poorly and apparent non-immunogenic tumors and induce a tumor-specific immune memory. J. Immunol. 145:3136–3143.
Atkins, M.B., Vachino, G., Tilg, H.J., Karp, D.D., Robert, N.J., Kappler, K., et al. (1992). I evaluation of thrice-daily intravenous bolus interleukin-4 in patients with refractory malignancy. J. Clin. Oncol. 10:1802–1809.
Margolin, K.A., Aronson, F., Sznol, M., Atkins, M.B., Dutcher, J.P., Fisher, R.I., et al. (1994). Recombinant human IL-4 in advanced renal cancer and malignant melanoma. J. Immunother. 15:147–153.
Van Snick, J. (1990). Interleukin-6: an overview. Annu. Rev. Immunol. 8:253–278.
Kishimoto, T. (1989). The biology of interleukin-6. Blood 74:1–10.
Kishimoto, T., Akira, S. and Taga, T. (1992). Interleukin-6 and its receptor. a paradigm for cytokines. Science (Wash. D.C.) 258:593–597.
Weber, J. (1993). Interleukin-6: multifunctional cytokine, in Biologic Therapy of Cancer, Updates, Volume 3 (V.T. Devita, S. Hellman, and S.A. Rosenberg, eds.), pp. 1–9, J.B. Lippincott, Philadelphia.
Mule, J.J., McIntosh, J.K., Jablons, D.M. and Rosenberg, S.A. (1990). Antitumor activity of recombinant interleukin-6 in mice. J. Exp. Med. 171:629–636.
Mule, J.J., Custer, M.C., Travis, W.D. and Rosenberg, S.A. (1992). Cellular mechanisms of the antitumor activity or recombinant IL-6 in mice. J. Immunol. 148:2622–2626.
Sosman, J.A., Aronson, F.R., Sznol, M., Atkins, M.B., Dutcher, J.P., Weiss, G.R., et al. (1997). Phase I trials of intravenous interleukin-6. Clin. Cancer Res. 3:39–46.
Weiss, G.R., Margolin, K.A., Sznol, M., Atkins, M.B., Oleksowicz, L., Isaacs, R., et al. (1995). A phase II study of a 120-hour continuous intravenous infusion of interleukin-6 for metastatic renal cell carcinoma. J. Immunother. 18:52–56.
Oleksowicz, L., Mrowiec, Z., Isaacs, R., Dutcher, J.P. and Puszkin, E. (1995). Morphologic and ultrastructural evidence for interleukin-6 induced platelet activation. Am. J. Hematol. 48:92–99.
Oleksowicz, L., Puszkin, E., Mrowiec, Z., Issacs, R. and Dutcher, J.P. (1996). Alterations in platelet function in patients receiving interleukin-6 as cytokine therapy. Cancer Invest. 14:307–316.
Trinchieri, G. (1994). Interleukin 12: a cytokine produced by antigen presenting cells with immunoregulatory functions in the generation of T helper cells type 1 and cytotoxic lymphocytes. Blood 84:4008–4013.
Brunda, M.J. (1994). Interleukin 12. J. Leukocyte Biol. 55:280–286.
Wolf, S.F., Sieburth, D. and Sypek, J. (1994). Interleukin 12: a key modulator of immune function. Stem Cells 12:154–160.
Brunda, M.J., Lusitro, L., Warrior, R., Wright, B.B., Hubbard, B.R., Murphy, M., et al. (1993). Antitumor and antimetastatic activity of interleukin-12 against murine tumors. J. Exp. Med. 178:1223–1229.
Brunda, M.J., Luistro, L., Hendrzak, J.A., Fountoulakis, M., Garotta, G. and Gately, M.K. (1995). Role of interferon — gamma in mediating the antitumor efficacy of interleukin-12. J. Immunother. 17:71–78.
Nastala, C.L., Edington, H.G., McKinney, T.G., Tahara, H., Nalesnik, M.A., Brunda, M.J., et al. (1994). Recombinant IL-12 administration induces tumor regression in association with IFN-gamma production. J. Immunol. 153:1697–1702.
Zou, J.-P., Yamamoto, N., Fuji, T., Takenaka, H., Kobayashi, M., Herrmann, S.H., et al. (1995). Systemic administration of rIL-12 induces complete tumor regression and protective immunity: response is correlated with a striking reversal of suppressed IFN-gamma production by anti-tumor T cells. Int. Immunol. 7:1135–1139.
Atkins, M.B., Robertson, M.J., Gordon, M., Lotze, M.T., DeCoste, M., DuBois, J.S., et al. (1997). Phase I evaluation of intravenous recombinant human interleukin-12 in patients with advanced malignancies. Clin. Cancer Res. 3:409–414.
Leonard, J.P., Sherman, M.L., Fisher, G.L., Buchanan, L.J., Larsen, G., Atkins, M.B., et al. (1997). Effects of single-dose interleukin-12 (IL-12) exposure on IL-12-associated toxicity and interferon-gamma production. Blood 90:2541–2548.
Rook, A.H., Wood, G.S., Yoo, E.K., Elenitsas, R., Kao, D.M., Sherman, M.L., et al. (1999). Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion regression and cytotoxic T-cell responses. Blood 94:902–908.
Pluda, J.M., Wyvill, K., Little, R., Lietzau, J., Shearer, G., Tosato, G., et al. (1999). A pilot/dose-finding study of interleukin-12 administered to patients with AIDS-associated Kaposi’s sarcoma. Proc. Am. Soc. Clin. Oncol. 18:547a.
Gascon, P. and Schwartz, R.A. (2000). Kaposi’s sarcoma. New treatment modalities. Dermatol. Clin. 18:169–175.
Gollob, J.A., Mier, J.W., Veenstra, K., McDermott, D.F., Cheng, D., Clay, M., et al. (2000). Phase I trial of twice weekly intravenous interleukin-12 in patients with metastatic renal cell cancer or malignant melanoma: ability to maintain IFN-γ induction is associated with clinical response. Clin. Cancer Res. 6:1678–1692.
Shanafelt, A.B., Lin, Y., Shanafelt, M.-C., Forte, C.P., Dubois-Stringfellow, N., Carter, C., et al. (2000). A T-cell selective interleukin-2 mutein exhibits potent antitumor activity and is well tolerated in vivo. Nature Biotechnol. 18:1197–1202.
Trump, D.L., Elson, P., Propert, K., Pontes, E., Crawford, G., Wilding, G., et al. (1996). Randomized controlled trial of adjuvant therapy with lymphoblastoid interferon in resected high-risk renal cell carcinoma. Proc. Am. Soc. Clin. Oncol. 15:253a.
McDermott, D., Flaherty, L., Clark, J., Weiss, G., Logan, T., Gordon, M., et al. (2001). A randomized phase III trial of high-dose interleukin-2 (IL2) versus subcutaneous IL2/interferon in patients with metastatic renal cell carcinoma. Proc. Am. Soc. Clin. Oncol. 20:172a.
Author information
Authors and Affiliations
Consortia
Corresponding author
Rights and permissions
About this article
Cite this article
Dutcher, J., Atkins, M.B., Margolin, K. et al. Kidney cancer: The cytokine working group experience (1986–2001). Med Oncol 18, 209–219 (2001). https://doi.org/10.1385/MO:18:3:209
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/MO:18:3:209