Interleukin 21: combination strategies for cancer therapy

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 (T H 17) 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. Interleukin 21 (IL21) is an immune-stimulating cytokine that has demonstrated antitumour activity in preclinical models and has recently entered clinical trials. Here, the authors discuss the antitumour effects of IL21 and describe strategies to combine IL21 with other drugs for future cancer therapies. 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; howeve