Skip to main content
SpringerLink
Log in

Interleukins 18 and 21: Biology, mechanisms of action toxicity, and clinical activity

  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Interleukins 18 and 21 have been described, and the effect of each upon immune response and experimental tumors in animals has been the subject of much recent work. Both interleukins have shown antitumor effects in animals, which in some models are striking for their duration, specificity, and ability to protect against rechallenge with the same tumor. These characteristics suggest immunologic involvement in the antitumor response, and several papers suggest involvement of both innate and adaptive immune mechanisms. Recent early phase I clinical trials in human cancer patients have demonstrated evidence of clinical response. This review discusses the biology, preclinical animal tumor model data, and early clinical trial findings.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Burnet FM: The concept of immunological surveillance. Prog Exp Tumor Res 1970, 13:1–27.

    PubMed  CAS  Google Scholar 

  2. Boon T, Coulie PG, Van den Eynde B: Tumor antigens recognized by T cells. Immunol Today 1997, 18:267–268.

    Article  PubMed  CAS  Google Scholar 

  3. Old LJ, Chen YT: New paths in human cancer serology. J Exp Med 1998, 187:1163–1167.

    Article  PubMed  CAS  Google Scholar 

  4. Marincola FM: Cancer vaccines: basic principles. Mechanisms of immune escape and immune tolerance. In Principles and Practice of the Biologic Therapy of Cancer, edn 3. Edited by Rosenberg SA. Philadelphia: Lippincott Williams & Wilkins; 2000:601–617.

    Google Scholar 

  5. Germain RN: MHC-dependent antigen processing and peptide presentation: providing ligands for T lymphocyte activation. Cell 1994, 76 28Januay:287–299.

    Article  PubMed  CAS  Google Scholar 

  6. Matzinger P: Tolerance, danger, and the extended family. Annu Rev Immunol 1994, 12:991–1045.

    PubMed  CAS  Google Scholar 

  7. Smyth MJ, Cretney E, Kershaw MH, Hayakawa Y: Cytokines in cancer immunity and immunotherapy. Immunol Rev 2004, 202:275–293. An excellent and up-to-date review of cytokines and their role in cancer immunology/immunotherapy.

    Article  PubMed  CAS  Google Scholar 

  8. Okamura H, Kawaguchi K, Shoji K, Kawade Y: High-level induction of gamma interferon with various mitogens in mice pretreated with Propionibacterium acnes. Infect Immun 1982, 38:440–443.

    PubMed  CAS  Google Scholar 

  9. Okamura H, Tsutsi H, Komatsu T, et al.: Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 1995, 378:88–91.

    Article  PubMed  CAS  Google Scholar 

  10. Ushio S, Namba M, Okura T, et al.: Cloning of the cDNA for human IFN-gamma-inducing factor, expression in Escherichia coli, and studies on the biologic activities of the protein. J Immunol 1996, 156:4274–4279.

    PubMed  CAS  Google Scholar 

  11. Bazan JF, Timans JC, Kastelein RA: A newly defined interleukin-1? Nature 1996, 379:591.

    Article  PubMed  CAS  Google Scholar 

  12. Gu Y, Kuida K, Tsutsui H, et al.: Activation of interferongamma inducing factor mediated by interleukin-1beta converting enzyme. Science 1997, 275:206–209.

    Article  PubMed  CAS  Google Scholar 

  13. Gracie JA, Robertson SE, McInnes IB: Interleukin-18. J Leukoc Biol 2003, 73:213–224. A good recent review of the overall biology of IL-18.

    Article  PubMed  CAS  Google Scholar 

  14. Vankayalapati R, Wizel B, Weis SE, et al.: Production of interleukin-18 in human tuberculosis. J Infect Dis 2000, 182:234–239.

    Article  PubMed  CAS  Google Scholar 

  15. Pirhonen J, Sareneva T, Kurimoto M, et al.: Virus infection activates IL-1 beta and IL-18 production in human macrophages by a caspase-1-dependent pathway. J Immunol 1999, 162:7322–7329.

    PubMed  CAS  Google Scholar 

  16. Kohno K, Kurimoto M: Interleukin 18, a cytokine which resembles IL-1 structurally and IL-12 functionally but exerts its effect independently of both. Clin Immunol Immunopathol 1998, 86:11–15. This is an excellent review of the early development of IL-18.

    Article  PubMed  CAS  Google Scholar 

  17. Reddy P: Interleukin-18: recent advances. Curr Opin Hematol 2004, 11:405–410.

    Article  PubMed  CAS  Google Scholar 

  18. Neighbors M, Xu X, Barrat FJ, et al.: A critical role for interleukin 18 in primary and memory effector responses to Listeria monocytogenes that extends beyond its effects on interferon gamma production. J Exp Med 2001, 194:343–354.

    Article  PubMed  CAS  Google Scholar 

  19. Helmby H, Takeda K, Akira S, Grencis RK: Interleukin (IL)-18 promotes the development of chronic gastrointestinal helminth infection by downregulating IL-13. J Exp Med 2001, 194:355–364.

    Article  PubMed  CAS  Google Scholar 

  20. Kaser A, Kaser S, Kaneider NC, et al.: Interleukin-18 attracts plasmacytoid dendritic cells (DC2s) and promotes Th1 induction by DC2s through IL-18 receptor expression. Blood 2004, 103:648–655.

    Article  PubMed  CAS  Google Scholar 

  21. Swain SL: Interleukin 18: tipping the balance towards a T helper cell 1 response. J Exp Med 2001, 194:F11-F14.

    Article  PubMed  CAS  Google Scholar 

  22. Micallef MJ, Tanimoto T, Kohno K, et al.: Interleukin 18 induces the sequential activation of natural killer cells and cytotoxic T lymphocytes to protect syngeneic mice from transplantation with Meth A sarcoma. Cancer Res 1997, 57:4557–4563. A second paper in which Micallef et al. demonstrated antitumor effects of IL-18 in tumor-bearing mice.

    PubMed  CAS  Google Scholar 

  23. Micallef MJ, Yoshida K, Kawai S, et al.: In vivo antitumor effects of murine interferon-gamma-inducing factor/ interleukin-18 in mice bearing syngeneic Meth A sarcoma malignant ascites. Cancer Immunol Immunother 1997, 43:361–367. Micallef et al. demonstrated antitumor effects of IL-18 in tumorbearing mice and suggested associated immunologic specificity and memory with important involvement of both NK and CD4+ T cells in the antitumor response.

    Article  PubMed  CAS  Google Scholar 

  24. Osaki T, Peron JM, Cai Q, et al.: IFN-gamma-inducing factor/IL-18 administration mediates IFN-gamma- and IL-12-independent antitumor effects. J Immunol 1998, 160:1742–1749. This paper also suggests involvement of NK and CD4+ T cells in the described IL-18 antitumor effects.

    PubMed  CAS  Google Scholar 

  25. Iwasaki T, Yamashita K, Tsujimura T, et al.: Interleukin-18 inhibits osteolytic bone metastasis by human lung cancer cells possibly through suppression of osteoclastic boneresorption in nude mice. J Immunother 2002, 25(Suppl1):S52-S60.

    Article  PubMed  CAS  Google Scholar 

  26. Yamashita K, Iwasaki T, Tsujimura T, et al.: Interleukin-18 inhibits lodging and subsequent growth of human multiple myeloma cells in the bone marrow. Oncol Rep 2002, 9:1237–1244.

    PubMed  CAS  Google Scholar 

  27. Okamoto T, Yamada N, Tsujimura T, et al.: Inhibition by interleukin-18 of the growth of Dunn osteosarcoma cells. J Interferon Cytokine Res 2004, 24:161–167.

    Article  PubMed  CAS  Google Scholar 

  28. Kikuchi T, Akasaki Y, Joki T, et al.: Antitumor activity of interleukin-18 on mouse glioma cells. J Immunother 2000, 23:184–189.

    Article  PubMed  CAS  Google Scholar 

  29. Akamatsu S, Arai N, Hanaya T, et al.: Antitumor activity of interleukin-18 against the murine T-cell leukemia/ lymphoma EL-4 in syngeneic mice. J Immunother 2002, 25(Suppl1):S28-S34.

    Article  PubMed  CAS  Google Scholar 

  30. Wigginton JM, Lee JK, Wiltrout TA, et al.: Synergistic engagement of an ineffective endogenous anti-tumor immune response and induction of IFN-gamma and Fas-ligand-dependent tumor eradication by combined administration of IL-18 and IL-2. J Immunol 2002, 169:4467–4474. This paper, along with that of Son et al. [31], suggests the importance of considering combination antitumor therapy with IL-18 and other cytokines.

    PubMed  CAS  Google Scholar 

  31. Son YI, Dallal RM, Lotze MT: Combined treatment with interleukin-18 and low-dose interleukin-2 induced regression of a murine sarcoma and memory response. J Immunother 2003, 26:234–240.

    Article  PubMed  CAS  Google Scholar 

  32. Cao R, Farnebo J, Kurimoto M, Cao Y: Interleukin-18 acts as an angiogenesis and tumor suppressor. FASEB J 1999, 13:2195–2202.

    PubMed  CAS  Google Scholar 

  33. Osaki T, Hashimoto W, Gambotto A, et al.: Potent antitumor effects mediated by local expression of the mature form of the interferon-gamma inducing factor, interleukin-18 (IL-18). Gene Ther 1999, 6:808–815.

    Article  PubMed  CAS  Google Scholar 

  34. Fukumoto H, Nishio M, Nishio K, et al.: Interferon-gammainducing factor gene transfection into Lewis lung carcinoma cells reduces tumorigenicity in vivo. Jpn J Cancer Res 1997, 88:501–505.

    PubMed  CAS  Google Scholar 

  35. Ju DW, Yang Y, Tao Q, et al.: Interleukin-18 gene transfer increases antitumor effects of suicide gene therapy through efficient induction of antitumor immunity. Gene Ther 2000, 7:1672–1679.

    Article  PubMed  CAS  Google Scholar 

  36. Tatsumi T, Gambotto A, Robbins PD, Storkus WJ: Interleukin 18 gene transfer expands the repertoire of antitumor Th1-type immunity elicited by dendritic cell-based vaccines in association with enhanced therapeutic efficacy. Cancer Res 2002, 62:5853–5858.

    PubMed  CAS  Google Scholar 

  37. Tatsumi T, Huang J, Gooding WE, et al.: Intratumoral delivery of dendritic cells engineered to secrete both interleukin (IL)-12 and IL-18 effectively treats local and distant disease in association with broadly reactive Tc1-type immunity. Cancer Res 2003, 63:6378–6386.

    PubMed  CAS  Google Scholar 

  38. Carrascal MT, Mendoza L, Valcarcel M, et al.: Interleukin-18 binding protein reduces B16 melanoma hepatic metastasis by neutralizing adhesiveness and growth factors of sinusoidal endothelium. Cancer Res 2003, 63:491–497.

    PubMed  CAS  Google Scholar 

  39. Cho D, Song H, Kim YM, et al.: Endogenous interleukin-18 modulates immune escape of murine melanoma cells by regulating the expression of Fas ligand and reactive oxygen intermediates. Cancer Res 2000, 60:2703–2709.

    PubMed  CAS  Google Scholar 

  40. Robertson MJ, Mier J, Logan TF, et al.: Tolerability and anti-tumor activity of recombinant human IL-18 (rhIL-18) administered as five daily intravenous infusions in patients with solid tumors. J Clin Oncol 2004, 23:76 (Suppl; abstr 2553).

    Google Scholar 

  41. Koch KM, Kwok D, McIntosh T, et al.: Pharmacokinetics and parmacodynamics of recombinant human IL-18 (rhIL-18) in patients with solid tumors. Eur J Cancer 2004 2(Suppl):82(abstract 267).

    Google Scholar 

  42. Robertson MJ, Kirkwood JM, Logan TF, et al.: Phase I study of recombinate human IL-18 (rhIL-18) administered as five daily intrvenous infusions every 28 days in patients with solid tumors. J Clin Oncol 2005, 23:2513 (Suppl; abstr 16).

    Article  Google Scholar 

  43. Parrish-Novak J, Dillon SR, Nelson A, et al.: Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 2000, 408:57–63. One of the original descriptions of IL-21.

    Article  PubMed  CAS  Google Scholar 

  44. Ozaki K, Kikly K, Michalovich D, et al.: Cloning of a type I cytokine receptor most related to the IL-2 receptor beta chain. Proc Natl Acad Sci U S A 2000, 97:11439–11444.

    Article  PubMed  CAS  Google Scholar 

  45. Parrish-Novak J, Foster DC, Holly RD, Clegg CH: Interleukin-21 and the IL-21 receptor: novel effectors of NK and T cell responses. J Leukoc Biol 2002, 72:856–863.

    PubMed  CAS  Google Scholar 

  46. Mehta DS, Wurster AL, Grusby MJ: Biology of IL-21 and the IL-21 receptor. Immunol Rev 2004, 202:84–95. An excellent recent review of IL-21 and its receptor.

    Article  PubMed  CAS  Google Scholar 

  47. Brenne AT, Baade RT, Waage A, et al.: Interleukin-21 is a growth and survival factor for human myeloma cells. Blood 2002, 99:3756–3762.

    Article  PubMed  CAS  Google Scholar 

  48. Nutt SL, Brady J, Hayakawa Y, Smyth MJ: Interleukin 21: a key player in lymphocyte maturation. Crit Rev Immunol 2004, 24:239–250.

    Article  PubMed  CAS  Google Scholar 

  49. Sivakumar PV, Foster DC, Clegg CH: Interleukin-21 is a T-helper cytokine that regulates humoral immunity and cell-mediated anti-tumour responses. Immunology 2004, 112:177–182.

    Article  PubMed  CAS  Google Scholar 

  50. Ugai S, Shimozato O, Kawamura K, et al.: Expression of the interleukin-21 gene in murine colon carcinoma cells generates systemic immunity in the inoculated hosts. Cancer Gene Ther 2003, 10(March):187–192.

    Article  PubMed  CAS  Google Scholar 

  51. Brady J, Hayakawa Y, Smyth MJ, Nutt SL: IL-21 induces the functional maturation of murine NK cells. J Immunol 2004, 172:2048–2058.

    PubMed  CAS  Google Scholar 

  52. Wang G, Tschoi M, Spolski R, et al.: In vivo antitumor activity of interleukin 21 mediated by natural killer cells. Cancer Res 2003, 63:9016–9022.

    PubMed  CAS  Google Scholar 

  53. Ma HL, Whitters MJ, Konz RF, et al.: IL-21 activates both innate and adaptive immunity to generate potent antitumor responses that require perforin but are independent of IFNgamma. J Immunol 2003, 171:608–615.

    PubMed  CAS  Google Scholar 

  54. Di Carlo E, Comes A, Orengo AM, et al.: IL-21 induces tumor rejection by specific CTL and IFN-gamma-dependent CXC chemokines in syngeneic mice. J Immunol 2004, 172:1540–1547.

    PubMed  Google Scholar 

  55. Nakano H, Kishida T, Asada H, et al.: Interleukin-21 triggers both cellular and humoral immune responses leading to therapeutic antitumor effects against head and neck squamous cell carcinoma. J Gene Med 2005, 8:90–99.

    Article  Google Scholar 

  56. Zeng R, Spolski R, Finkelstein SE, et al.: Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J Exp Med 2005, 201:139–148.

    Article  PubMed  CAS  Google Scholar 

  57. Moroz A, Eppolito C, Li Q, et al.: IL-21 enhances and sustains CD8+ T cell responses to achieve durable tumor immunity: comparative evaluation of IL-2, IL-15, and IL-21. J Immunol 2004, 173:900–909. This paper suggests substantial antitumor activity for systemic IL-21 compared with other cytokines and suggests a possible related mechanism in increased T-cell survival.

    PubMed  CAS  Google Scholar 

  58. Curti B, Redman BG, Thompson JA, Sievers EL: Preliminary tolerability and anti-tumor activity of intravenous recombinate human interleukin-21 (IL-2) in patients with metastatic melanoma and metastatic renal cell carcinoma. J Clin Oncol 2005, 23:2502 (Suppl; abstr).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Indiana University Cancer Center, 535 Barnhill Drive, RT 473, 46202, Indianapolis, IN, USA

    Theodore F. Logan MD

Authors
  1. Theodore F. Logan MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael J. Robertson MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Theodore F. Logan MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Logan, T.F., Robertson, M.J. Interleukins 18 and 21: Biology, mechanisms of action toxicity, and clinical activity. Curr Oncol Rep 8, 114–119 (2006). https://doi.org/10.1007/s11912-006-0046-0

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11912-006-0046-0

Keywords

Search

Navigation