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Kidney cancer: The cytokine working group experience (1986–2001)

Part II: Management of IL-2 toxicity and studies with other cytokines

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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.

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References

  1. 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.

    PubMed  CAS  Google Scholar 

  2. 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.

    PubMed  CAS  Google Scholar 

  3. 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.

    PubMed  CAS  Google Scholar 

  4. 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.

    PubMed  CAS  Google Scholar 

  5. 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.

    PubMed  CAS  Google Scholar 

  6. 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.

    PubMed  CAS  Google Scholar 

  7. 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.

    Article  PubMed  CAS  Google Scholar 

  8. 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.

    Article  Google Scholar 

  9. 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.

    PubMed  CAS  Google Scholar 

  10. 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.

    Google Scholar 

  11. 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.

    Article  PubMed  CAS  Google Scholar 

  12. Paul, W.E. (1984). Nomenclature of lymphokines which regulate B-lymphocytes. Mol. Immunol. 21:343–349.

    Article  PubMed  CAS  Google Scholar 

  13. 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.

    Article  PubMed  CAS  Google Scholar 

  14. 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.

    PubMed  CAS  Google Scholar 

  15. 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.

    PubMed  CAS  Google Scholar 

  16. 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.

    PubMed  CAS  Google Scholar 

  17. 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.

    Article  CAS  Google Scholar 

  18. Van Snick, J. (1990). Interleukin-6: an overview. Annu. Rev. Immunol. 8:253–278.

    Article  PubMed  Google Scholar 

  19. Kishimoto, T. (1989). The biology of interleukin-6. Blood 74:1–10.

    PubMed  CAS  Google Scholar 

  20. Kishimoto, T., Akira, S. and Taga, T. (1992). Interleukin-6 and its receptor. a paradigm for cytokines. Science (Wash. D.C.) 258:593–597.

    Article  CAS  Google Scholar 

  21. 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.

    Google Scholar 

  22. 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.

    Article  PubMed  CAS  Google Scholar 

  23. 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.

    PubMed  CAS  Google Scholar 

  24. 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.

    PubMed  CAS  Google Scholar 

  25. 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.

    Article  CAS  Google Scholar 

  26. 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.

    PubMed  CAS  Google Scholar 

  27. 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.

    PubMed  CAS  Google Scholar 

  28. 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.

    PubMed  CAS  Google Scholar 

  29. Brunda, M.J. (1994). Interleukin 12. J. Leukocyte Biol. 55:280–286.

    PubMed  CAS  Google Scholar 

  30. Wolf, S.F., Sieburth, D. and Sypek, J. (1994). Interleukin 12: a key modulator of immune function. Stem Cells 12:154–160.

    Article  PubMed  CAS  Google Scholar 

  31. 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.

    Article  PubMed  CAS  Google Scholar 

  32. 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.

    Article  CAS  Google Scholar 

  33. 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.

    PubMed  CAS  Google Scholar 

  34. 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.

    Article  PubMed  CAS  Google Scholar 

  35. 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.

    PubMed  CAS  Google Scholar 

  36. 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.

    PubMed  CAS  Google Scholar 

  37. 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.

    PubMed  CAS  Google Scholar 

  38. 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.

    Google Scholar 

  39. Gascon, P. and Schwartz, R.A. (2000). Kaposi’s sarcoma. New treatment modalities. Dermatol. Clin. 18:169–175.

    Article  PubMed  CAS  Google Scholar 

  40. 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.

    PubMed  CAS  Google Scholar 

  41. 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.

    Article  CAS  Google Scholar 

  42. 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.

    Google Scholar 

  43. 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.

    Google Scholar 

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Correspondence to Janice Dutcher M.D..

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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

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