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Interleukin 21: combination strategies for cancer therapy

An Erratum to this article was published on 01 March 2008

Key Points

  • Immunotherapy has increasingly become a focus area for cancer therapy, which has been stimulated by the recent advances in our understanding of the immune system. The ability of immunotherapy to selectively target malignant cells makes this an attractive alternative to conventional chemotherapy.

  • Interleukin 21 (IL21) is a cytokine that has effects on both the innate and adaptive immune system. IL21 augments antigen-driven proliferation and activation of cytotoxic (CD8+) T cells, and also promotes differentiation of T-helper 17 (TH17) cells, natural killer (NK) cell activation, B-cell proliferation and immunoglobulin class switching.

  • Several studies in mouse tumour models have demonstrated antitumour effects of IL21. These are mediated primarily through cytotoxic T cells and NK cells, whereas effects on helper (CD4+) T cells and B cells may contribute to a lesser extent.

  • For optimal therapeutic effect IL21 will most likely need to be combined with other therapies. Synergistic antitumour efficacy may be obtained when combining with other immunotherapies, such as other cytokines, vaccines, cytotoxic T-lymphocyte antigen 4 (CTLA4) blockade or NKT cell activation.

  • Combining IL21 with tumour-targeted antibodies may enhance killing through antibody-dependent cellular cytotoxicity, thereby providing a rationale for this combination.

  • Tumour necrosis and apoptosis induced by cytostatics, tyrosine kinase inhibitors or tumour necrosis factor-related apoptosis-inducing ligand (TRAIL; also known as TNFSF10) agonists may stimulate antitumour immune responses. Immune stimulators such as IL21 may be used to enhance this response into a clinically measurable response.

  • Phase I trials of IL21 in patients with stage IV metastatic melanoma have recently been completed, showing an acceptable safety profile and clinical signs of activity. New trials with IL21 in combination with sorafenib, cetuximab or rituximab are currently taking place.

Abstract

In the past 20 years researchers have attempted to activate the host immune defence system to kill tumour cells and eradicate cancer. In some cases, the response of patients to immunotherapy has been extremely successful; however, other trials have shown disappointing results, and so there is a clear need for more effective therapies that can effectively adjunct conventional approaches. Interleukin 21 (IL21) is a new immune-stimulating cytokine that has demonstrated antitumour activity in several preclinical models, and has recently undergone Phase I trials in metastatic melanoma and renal cell carcinoma. Here, we provide an overview of the antitumour effects of IL21 and describe strategies to combine IL21 with other drugs for future cancer therapies.

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Figure 1: Pleiotropic immune modulation by IL21.
Figure 2: Potential combination strategies with IL21 therapy.

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Correspondence to Mark J. Smyth or Pallavur V. Sivakumar.

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Competing interests

K.S. is employed by and owns shares in Novo Nordisk A/S, which is involved in the commercialization of recombinant IL21.

P.V.S. and D.H. are employees and stock holders of ZymoGenetics Inc., which is involved in the modulation and commercialization of therapeutic proteins for the prevention and treatment of human diseases, including recombinant IL21.

M.K. and M.J.S. declare no competing financial interests.

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DATABASES

OMIM

Breast cancer

cervical cancer

colorectal cancer

non-Hodgkin's lymphoma

renal cell carcinoma

FURTHER INFORMATION

ClinicalTrials.gov database

European Clinical Trials database

Glossary

Natural killer (NK) cell

A lymphocyte subset that is part of the innate immune response and is able to recognize virus-infected or transformed cells that lack major histocompatibility class class I expression. In contrast to T cells, NK cells do not require activation but are able to immediately kill these cells.

Antibody-dependent cellular cytotoxicity

(ADCC). Describes the phenomenon that Fc-γ receptor (FcγR)-expressing leukocytes can bind to the Fc moiety of an antibody, leading to killing of the cell bound by the antibody.

Dendritic cell

An antigen-presenting cell found in T-cell areas of lymphoid tissues, but also as a minor cellular component in most tissues. They have a branched or dendritic morphology and are the most potent stimulators of T-cell responses.

FOXP3

A member of the forkhead/winged-helix family of transcriptional regulators. It functions as the master regulator in the development and function of regulatory T cells.

Regulatory T-cell

Regulatory T (TReg) cells are a CD4+ T-cell subset that are characterized by the expression of CD25 (interleukin 2 receptor-α (IL2Rα) subunit) and FOXP3. TReg cells are powerful suppressors of adaptive immune responses, are commonly found in many tumours and it is thought that the activity of TReg cells is a major reason of why many immunotherapies have failed to show clinical responses.

Macrophage

One of the main types of professional phagocytes. Macrophages are long-lived and detrimental for many microbial pathogens. Intracellular bacteria, can survive within the macrophages. They can mediate antibody-dependent cellular cytotoxicity through phagocytosis.

Isotype switching

A region-specific recombination process that occurs in antigen-activated B cells that results in a change in the class of antibody that is produced — from immunoglobulin M (IgM) to either IgG, IgA or IgE. This creates flexibility in the immune response, whereby a single antibody can be used by several different parts of the immune system.

OT-1 TCR-transgenic mice

Transgenic mice that have a T-cell receptor (TCR) specific for a major histocompatibility-class-I-restricted peptide derived from ovalbumin.

RenCa and 4T1 tumour models

RenCa is a mouse renal cell tumour line that was derived from a BALB/c mouse and is used as a surrogate model for renal cell carcinoma in mice. 4T1 is mouse breast carcinoma cell line derived from a tumour in BALB/c mouse and is used as a surrogate for mammary carcinoma in mice.

Invariant NKT (iNKT) cell

A rare subset of lymphocytes that expresses an invariant T-cell receptor that recognizes certain glycolipids when bound to the major histocompatibility complex class I-like molecule, CD1d. Through secretion of cytokines they are powerful modulators of adaptive immune responses, and they can also enhance activation of natural killer cells.

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Skak, K., Kragh, M., Hausman, D. et al. Interleukin 21: combination strategies for cancer therapy. Nat Rev Drug Discov 7, 231–240 (2008). https://doi.org/10.1038/nrd2482

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