Interleukin-18 in cancer immunology and immunotherapy

ABSTRACTIntroduction Interleukin-18 (IL-18) is a myeloid leukocyte inflammatory mediator whose main known function is to elicit IFNγ secretion from T and NK cells.Areas covered This 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 opinion IL-18 certainly holds promise for immunotherapy in combination with other agents and for local approaches.KEYWORDS: Interleukin-18decoy resistant IL-18combination strategiesmRNACAR-T cellsDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Article highlightsIL-18 may play double-edged roles in cancer immunobiologyApplicability of recombinant IL-18 for cancer treatment has been tested in preclinical studies and in clinical trials.The therapeutic activity of IL-18 is limited by IL-18BP, a natural decoy regulator of IL-18 bioactivity.Decoy-resistant variants of IL-18 (DR-18), which cannot bind to IL-18BP, have been developed as novel therapeutic agents to efficaciously treat mouse tumors and are being tested in the clinic.IL-18 gene-transfer increases the efficacy of various adoptive T-cell therapies in mouse models.Armoring CAR-T cells with IL-18 is safe and preliminary clinical results against hematological malignancies are promising.Combination approaches based on local delivery of mRNAs encoding IL-12 with DR-18 have achieved promising efficacy against mouse tumor models.Engineering antitumor T cells with mRNAs encoding DR-18 and IL-12 achieves synergistic preclinical therapeutic activity.AbbreviationsInterleukin-18 (IL-18), interferon-γ (IFNγ), interleukin-12 (IL-12), IL-18 binding protein (IL-18BP), decoy resistant IL-18 (DR-18), tumor necrosis factor (TNF), dendritic cells (DCs), dextran sulfate sodium (DSS), vascular endothelial growth factor (VEGF), Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF), chimeric antigen receptor (CAR), T cell receptor (TCR), programmed cell death protein-1 (PD-1), The Cancer Genome Atlas (TCGA), Food and Drug Administration (FDA), tumor infiltrating lymphocytes (TILs), adoptive therapy (ACT)Declaration of interestI Melero reports grants and personal fees from Genmab, Bristol Myers Squibb, Roche, AstraZeneca, and Pharmamar and personal fees from F-Star, Numab, Pieris, Boehringer Ingelheim, Gossamer, Alligator, Hotspot, Biolinerx, Bioncotech, Dompe, Highlight therapeutics, Bright Peaks and Boston Therapeutics outside the submitted work.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.AcknowledgementsCritical reading and scientific discussion with Drs Miguel F. Sanmamed, Alvaro Teijeira, and Maite Alvarez are acknowledged as well as support from Dr. Belen Palencia.Figure 1. Scheme of IL-18 biosynthesis, signal transduction in target T and NK cells and effects on the tumor microenvironment that can be neutralized by IL-18BP.Display full sizeFigure 2. Ways to exploit IL-18 engineered forms that resist IL-18BP to be used in cancer immunotherapy strategies.Display full sizeAdditional informationFundingThis project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 765394. This study was supported by Spanish Ministry of Economy and Competitiveness and Spanish Ministry of Research (MINECO SAF2014-52361-R and SAF 2017-83267-C2-1R MCIN/AEI/10.13039/501100011033/y por FEDER Una manera de hacer Europa and PID2020-112892RB-100, PID2020-113174-RA-100 MCIN/AEI/10.13039/501100011033, Cancer Research Institute under the CRI-CLIP, This work was supported by Instituto de Salud Carlos III (AC16/00015) and European Funds for Regional Development (EFRD) under the TRANSCAN-2 Programme, and Cancer Research UK [C18915/A29362], FCAECC and AIRC under the Accelerator Award Programme, Gobierno de Navarra Salud, Gobierno de Navarra Proyecto ARNMUNE Ref: 0011–1411-2023, Mark Foundation and "MINCITH. Metabolic requirements for immune INfiltration in effective Cancer ImmunoTHerapy" AYUDAS FUNDACIÓN BBVA A EQUIPOS DE INVESTIGACION CIENTIFICA 2019" Fundación BBVA and Fundación Olga Torres. This work was supported by Instituto de Salud Carlos III (PI22/00147) co-financed by Fondos Feder. Work produced with the support of a 2022 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation.