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Review
. 2017 Oct:190:159-168.
doi: 10.1016/j.imlet.2017.08.010. Epub 2017 Aug 16.

The potential and promise of IL-15 in immuno-oncogenic therapies

Tanya O Robinson  1 , Kimberly S Schluns  2
Affiliations
Review

The potential and promise of IL-15 in immuno-oncogenic therapies

Tanya O Robinson et al. Immunol Lett. 2017 Oct.

Abstract

This review provides an in-depth description of the preclinical and clinical studies demonstrating the effectiveness and limitations of IL-15 and IL-15 analogs given as an exogenous immuno-oncology agent. IL-15 is a cytokine that primarily stimulates the proliferation and cytotoxic functions of CD8T cells and NK cells leading to enhanced anti-tumor responses. While initially showing promise as a cancer therapeutic, the efficacy of IL-15 was limited by its short in vivo half-life. More recently, various approaches have been developed to improve the in vivo half-life and efficacy of IL-15, largely by generating IL-15/IL-15Rα conjugates. These new IL-15 based agents renew the prospect of IL-15 as a cancer immunotherapeutic agent. While having some efficacy in inducing tumor regression as a monotherapy, IL-15 agents also show great potential in being used in combination with other immuno-oncological therapies. Indeed, IL-15 used in combination therapy yields even better anti-tumor responses and prolongs survival than IL-15 treatment alone in numerous murine cancer models. The promising results from these preclinical studies have led to the implementation of several clinical trials to test the safety and efficacy of IL-15-based agents as a stand-alone treatment or in conjunction with other therapies to treat both advanced solid tumors and hematological malignancies.

Keywords: ALT-803; Clinical trials; Cytotoxic lymphocytes; IL-15; Immunotherapy; Soluble IL-15 complexes.

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Figures

Fig. 1
Fig. 1
IL-15 and IL-15 agonists used in immunotherapy. Cartoon depicts the multiple IL-15-based agents that are used to stimulate cytotoxic T cell and NK cell responses. rIL-15 was the first form of IL-15 to be examined in vivo. When administered, rIL-15 is believed to predominantly bind to cell surface IL-15Rα where it is transpresented to IL-15 responsive cells. Heterodimeric IL-15 is natural form of IL-15 that is cleaved from cells and can stimulate responses independent of cell interactions. Heterodimeric hIL-15 is being produced as a therapeutic by Novartis. RLI (Cytune Pharmaceuticals) is a fusion protein consisting of IL-15 linked to the sushi (cytokine-binding) domain of the IL-15Rα that can act as a soluble IL-15 agonist. IL-15/IL-15Rα-Fc complexes are generated by mixing commercially available IL-15Rα-Fc chimeric fusion protein with rIL-15 and have been used extensively in preclinical studies. ALT-803 (Altor Pharmaceutical) is an IL-15 superagonist consisting of mutated IL-15 (asparagine replaced with an aspartic residue), which has an increased affinity for CD122-expressing immune cells, linked to the sushi domain of the IL-15Rα that is fused to an Fc fragment. The IL-15 signals mediated by these IL-15 agonists is speculated to range in strength and duration as depicted by the bottom triangle. Signal strength and duration increases with increased abundance of agonist, increased in vivo half-life (imparted by IL-15 binding to IL-15Rα and presence of an Fc fragment), dimerization of the agonists, and increased affinity for the IL-2Rβ/γC complex (imparted by IL-15 binding to the sushi domain and the mutation present in ALT-803).
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