Evidence map›Paper›PMID 41520178›Full record

ArticleMolecular therapy : the journal of the American Society of Gene Therapy2026

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

Gabriel A Barragán Bravo, David A de la Cerda, Elisa Landoni, Kshiti Dholakia, Piotr Humeniuk, Leidy D Caraballo Galva, Ying Wang, Gengwen Tian, Boning Yang, Linjie Guo and 13 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

23 authors.

Gabriel A Barragán BravoCenter for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
David A de la CerdaCenter for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Elisa LandoniLineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Kshiti DholakiaCenter for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Piotr HumeniukCenter for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Leidy D Caraballo GalvaCenter for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Ying WangCenter for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Gengwen TianCenter for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Boning YangCenter for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Linjie GuoCenter for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Michael S WoodCenter for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Xavier RiosCenter for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Xin XuCenter for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Amy N CourtneyCenter for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Erica J Di PierroCenter for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Joan JacobCenter for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Yi-Han LiCenter for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Akshaya AdaikkalavanCenter for Advanced Innate Cell Therapy, Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Norihiro WatanabeCenter 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.
Sufeng MaoLester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
George MilesLester 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.
Gianpietro DottiLineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Leonid S MetelitsaCenter 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: lsmeteli@texaschildrens.org.

Funding

Tumor BiologyP30CA125123 · NCI · BAYLOR COLLEGE OF MEDICINE · PI Suzanne AW Fuqua · 2007 to 2026
$73.9M
Tissue ResourceP50CA126752 · NCI · BAYLOR COLLEGE OF MEDICINE · PI MALCOLM K. BRENNER, HELEN E HESLOP · 2007 to 2026
$51.4M
Tuning CAR-T cell functionR01CA247436 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DOTTI, GIANPIETRO · 2021 to 2025
$2.4M
CAR NKT Cell Immunotherapy of NeuroblastomaR01CA262250 · NCI · BAYLOR COLLEGE OF MEDICINE · PI Leonid S Metelitsa · 2021 to 2026
$2.2M
S10 Shared Instrument Grant - Leica Aperio Digital Scanner GT450S10OD028671 · OD · BAYLOR COLLEGE OF MEDICINE · PI MILES, GEORGE · 2020 to 2020
$477k
NCI NIH HHS P30 CA125123NCI NIH HHS P50 CA126752NCI NIH HHS R01 CA247436NCI NIH HHS R01 CA262250NIH HHS S10 OD028671
6 · The paper itself

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.

Indexed as

Immunotherapy, AdoptiveInterleukin-18Natural Killer T-CellsReceptors, Chimeric AntigenAnimalsCell Line, TumorCytotoxicity, ImmunologicHumansInterleukin-15Metabolic ReprogrammingMiceXenograft Model Antitumor AssaysIL15 protein, humanInterleukin-15Interleukin-18Receptors, Chimeric AntigenCARIL-15IL-18metabolismnatural killer T cellneuroblastoma

Identifiers

PMID41520178
PMCPMC12882818

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.