Interleukin-18 in cancer immunology and immunotherapy.

IntroductionInterleukin-18 (IL-18) is a myeloid leukocyte inflammatory mediator whose main known function is to elicit IFNγ secretion from T and NK cells.Areas coveredThis function offers potential in cancer immunotherapy but as a single treatment, preclinical and clinical antitumor activities are modest. IL-18 bioactivity is chiefly downregulated by a decoy soluble receptor named IL18-binding protein (IL-18BP) that is induced by IFNγ as a negative feedback mechanism. Recent advances indicate promising efficacy of IL-18 at armoring CAR-T cells for the treatment of hematological malignancies. Preclinical research has also yielded IL-18 constructs that do not bind IL-18BP but have preserved activity on the receptor and exert markedly increased antitumor effects. Indeed, agents of this kind are undergoing clinical trials. The synergistic effects of IL-18 and IL-12 in combination to induce IFNγ are extremely potent but are toxic if systemically delivered. In mouse models, IL-12 and decoy-resistant variants of IL-18 can be efficaciously used as local treatments for tumors by exploiting mRNA intratumoral co-delivery. Moreover, antitumor T cells can be transiently engineered with mRNAs encoding this combination of cytokines to attain efficacious synergistic effects also upon intratumoral delivery.Expert opinionIL-18 certainly holds promise for immunotherapy in combination with other agents and for local approaches.