ArticleMolecular therapy : the journal of the American Society of Gene Therapy2024
Granzyme B-activated IL18 potentiates αβ and γδ CAR T cell immunotherapy in a tumor-dependent manner.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed.
- Next-generation LMP2A-targeting TCR-recombinant T cells with inducible IL-18 expression to treat EBV-associated malignancies.Molecular therapy. Oncology · 2026Article
- Engineering the next generation of cellular therapies for solid tumors: multi-specific armored CARs and TME reprogramming strategies.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Interleukin-18 armours antitumour immune effectors.Nature reviews. Immunology · 2026Review
- Engineering CAR-Vδ2 T cells to boost persistence and anti-tumor function.bioRxiv : the preprint server for biology · 2026Article
- IL-18 metabolically reprograms CAR-expressing natural killer T cells and enhances their antitumor activity.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Re-Tooling of γδ T Cells for Cancer Immunotherapy Using Advanced Manufacturing and Genetic Engineering.Cells · 2026Review
- Single-cell and spatial transcriptome profiling identifies cellular heterogeneity and immunosuppressive tumor microenvironment in inflammatory breast cancer.Journal of advanced research · 2026Article
- Cytokine-Engineered Chimeric Antigen Receptor-T Cell Therapy: How to Balance the Efficacy and Toxicity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- How can we balance risk and benefit of interleukin-18 armored T cell therapies?Experimental biology and medicine (Maywood, N.J.) · 2026Review
- Tumor Microenvironment Onmyoji: Cytokines with Dual Protumor and Antitumor Roles.Cancer communications (London, England) · 2026Review
- Cytokine Engineering in CAR-T Cell Therapy: Next-Generation Strategies.Immune network · 2025Review
- In vivo CAR-T cell engineering: concept, research progress, potential challenges and enhancement strategies.Experimental hematology & oncology · 2025Review
- Cytokine-mediated regulation of immune cell metabolic pathways in the tumor microenvironment.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Recent advances in universal chimeric antigen receptor T cell therapy.Journal of hematology & oncology · 2025Review
- The causal relationship between inflammatory cytokines and lung cancer: a two-sample bidirectional mendelian randomization study.Discover oncology · 2025Article
- Harnessing the immunotherapeutic potentials of gamma delta T cells against hematological malignancies.HemaSphere · 2025Review
- Engineering CAR-T Therapeutics for Enhanced Solid Tumor Targeting.Advanced materials (Deerfield Beach, Fla.) · 2025Review
- Metabolic reprogramming of CAR T cells: a new frontier in cancer immunotherapy.Frontiers in immunology · 2025Review
- Current strategies for armoring chimeric antigen receptor T-cells to overcome barriers of the solid tumor microenvironment.Frontiers in immunology · 2025Review
- Targeting highly attenuated IL-18 to PD-1 for enhanced anti-tumor activity.Frontiers in immunology · 2025Article
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Authors and funding
7 authors.
Funding
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Abstract
Interleukin (IL)18 is a potent pro-inflammatory cytokine that is activated upon caspase 1 cleavage of the latent precursor, pro-IL18. Therapeutic T cell armoring with IL18 promotes autocrine stimulation and positive modulation of the tumor microenvironment (TME). However, existing strategies are imperfect since they involve constitutive/poorly regulated activity or fail to modify the TME. Here, we have substituted the caspase 1 cleavage site within pro-IL18 with that preferred by granzyme B, yielding GzB-IL18. We demonstrate that GzB-IL18 is constitutively released but remains functionally latent unless chimeric antigen receptor (CAR) T cells are activated, owing to concomitant granzyme B release. Armoring with GzB-IL18 enhances cytolytic activity, proliferation, interferon (IFN)-γ release, and anti-tumor efficacy by a similar magnitude to constitutively active IL18. We also demonstrate that GzB-IL18 provides a highly effective armoring strategy for γδ CAR T cells, leading to enhanced metabolic fitness and significant potentiation of therapeutic activity. Finally, we show that constitutively active IL18 can unmask CAR T cell-mediated cytokine release syndrome in immunocompetent mice. By contrast, GzB-IL18 promotes anti-tumor activity and myeloid cell re-programming without inducing such toxicity. Using this stringent system, we have tightly coupled the biological activity of IL18 to the activation state of the host CAR T cell, favoring safer clinical implementation of this technology.
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