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

•Interleukin 15 (IL-15) is immunostimulatory factor targeting CD8 T cells and NK cells that can promote anti-tumor responses and thus can be included among the arsenal for immuno-oncology therapies.•While rIL-15 initially showed promise as a cancer immuno-therapeutic agent, its utility is limited by a short in vivo half-life and the high doses required for efficacy.•Noncovalent association of IL-15 with IL-15Rα generates IL-15 agonists with increased stability, enhanced in vivo potency, and superior anti-tumor responses.•Multiple formulations of soluble IL-15IL-15Rα complexes are currently being investigated in clinical trials for therapeutic efficacy of numerous cancer types and in combination with other immunotherapies. 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.