Heterodimeric IL-15 in Cancer Immunotherapy

SIMPLE SUMMARY: The rapidly expanding field of cancer immunotherapy uses diverse technologies, including cytokines, T cells, and antibody administration, with the aim to induce effective immune responses leading to tumor control. Interleukin-15 (IL-15), a cytokine discovered in 1994, supports the homeostasis of cytotoxic immune cells and shows promise as an anti-tumor agent. Many studies have elucidated IL-15 synthesis, regulation and biological function and explored its therapeutic efficacy in preclinical cancer models. Escherichia coli-derived single-chain IL-15 was tested in the first in-human trial in cancer patients. Its effects were limited by the biology of IL-15, which in vivo comprises a complex of the IL-15 chain with the IL-15 receptor alpha (IL-15Rα) chain, together forming the IL-15 heterodimer (hetIL-15). Currently, single-chain IL-15 and several heterodimeric IL-15:IL-15Rα variants (hetIL-15, N-803 and RLI) are being tested in clinical trials. This review presents a summary of contemporary preclinical and clinical research on IL-15. ABSTRACT: Immunotherapy has emerged as a valuable strategy for the treatment of many cancer types. Interleukin-15 (IL-15) promotes the growth and function of cytotoxic CD8(+) T and natural killer (NK) cells. It also enhances leukocyte trafficking and stimulates tumor-infiltrating lymphocytes expansion and activity. Bioactive IL-15 is produced in the body as a heterodimeric cytokine, comprising the IL-15 and the so-called IL-15 receptor alpha chain that are together termed “heterodimeric IL-15” (hetIL-15). hetIL-15, closely resembling the natural form of the cytokine produced in vivo, and IL-15:IL-15Rα complex variants, such as hetIL-15Fc, N-803 and RLI, are the currently available IL-15 agents. These molecules have showed favorable pharmacokinetics and biological function in vivo in comparison to single-chain recombinant IL-15. Preclinical animal studies have supported their anti-tumor activity, suggesting IL-15 as a general method to convert “cold” tumors into “hot”, by promoting tumor lymphocyte infiltration. In clinical trials, IL-15-based therapies are overall well-tolerated and result in the expansion and activation of NK and memory CD8(+) T cells. Combinations with other immunotherapies are being investigated to improve the anti-tumor efficacy of IL-15 agents in the clinic.