2. Academic Validation
  3. IL-18 metabolically reprograms CAR-expressing natural killer T cells and enhances their antitumor activity

IL-18 metabolically reprograms CAR-expressing natural killer T cells and enhances their antitumor activity

  • Mol Ther. 2026 Jan 10:S1525-0016(26)00001-8. doi: 10.1016/j.ymthe.2026.01.001.
Gabriel A Barragán Bravo 1,  David A de la Cerda 1,  Elisa Landoni 2,  Kshiti Dholakia 1,  Piotr Humeniuk 1,  Leidy D Caraballo Galva 1,  Ying Wang 1,  Gengwen Tian 1,  Boning Yang 1,  Linjie Guo 1,  Michael S Wood 1,  Xavier Rios 1,  Xin Xu 1,  Amy N Courtney 1,  Erica J Di Pierro 1,  Joan Jacob 1,  Yi-Han Li 1,  Akshaya Adaikkalavan 1,  Norihiro Watanabe 3,  Sufeng Mao 4,  George Miles 5,  Gianpietro Dotti 2,  Leonid S Metelitsa 6
Affiliations

Affiliations

  • 1 Center for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 2 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
  • 3 Center for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
  • 4 Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • 5 Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 6 Center for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: [email protected].
PMID: 41520178 DOI: 10.1016/j.ymthe.2026.01.001
Abstract

Invariant natural killer T cells (NKTs) have intrinsic antitumor properties that make them promising candidates for chimeric antigen receptor (CAR) immunotherapies. Transgenic cytokine expression can enhance cellular therapy potency, and we hypothesized that co-expressing interleukin-18 (IL-18) alone or with IL-15 would boost CAR-NKT therapeutic potential. To test this, we generated retroviral constructs expressing IL-15 and/or IL-18 with an inducible caspase-9 safety switch and co-transduced them with a GD2-specific CAR into human NKTs. Co-expression of IL-18 or IL-15/IL-18 increased CAR-NKT cytotoxicity, proliferation, and cytokine secretion in vitro compared to IL-15 alone. IL-18 also enhanced GPC3.CAR and CD19.CAR NKT activity against hepatocellular carcinoma and B cell leukemia cells, respectively. In a metastatic neuroblastoma model, IL-18-expressing GD2.CAR-NKTs controlled tumors more effectively than IL-15-only cells, but mice in the IL-15/IL-18 group developed severe toxicities not observed in the IL-18-only group. Mechanistically, IL-18 induced a transcriptional program distinct from IL-15, marked by lower exhaustion signatures and enrichment of metabolic pathways. Finally, targeted metabolomics showed that IL-18 drives broad metabolic reprogramming in CAR-NKTs including increased Oxidative Phosphorylation, glycolysis, glutaminolysis, and purine metabolism. These findings support the use of IL-18 in developing the next generation of cytokine-armed CAR-NKT Cancer immunotherapies.

Keywords

CAR; IL-15; IL-18; metabolism; natural killer T cell; neuroblastoma.

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