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| Home > Institute Collections > W500 > Synthetic promoters to induce immune-effectors into the tumor microenvironment. |
| Home > Institute Collections > W500 > Synthetic promoters to induce immune-effectors into the tumor microenvironment. |
| Journal Article | DKFZ-2025-02404 |
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2021
Springer Nature
London
Abstract: Harnessing the immune-system to eradicate cancer is becoming a reality in recent years. Engineered immune cells, such as chimeric antigen receptor (CAR) T cells, are facing the danger of an overt life-threatening immune response due to the ON-target OFF-tumor cytotoxicity and Cytokine Release Syndrome. We therefore developed synthetic promoters for regulation of gene expression under the control of inflammation and Hypoxia-induced signals that are associated with the tumor microenvironment (TME). We termed this methodology as chimeric-antigen-receptor-tumor-induced-vector (CARTIV). For proof of concept, we studied synthetic promoters based on promoter-responsive elements (PREs) of IFNγ, TNFα and hypoxia; triple PRE-based CARTIV promoter manifested a synergistic activity in cell-lines and potent activation in human primary T-cells. CARTIV platform can improve safety of CAR T-cells or other engineered immune-cells, providing TME-focused activity and opening a therapeutic window for many tumor-associated antigens that are also expressed by non-tumor healthy tissues.
Keyword(s): Animals (MeSH) ; Breast Neoplasms: genetics (MeSH) ; Breast Neoplasms: immunology (MeSH) ; Breast Neoplasms: metabolism (MeSH) ; Breast Neoplasms: therapy (MeSH) ; Cell Line, Tumor (MeSH) ; Female (MeSH) ; Gene Expression Regulation, Neoplastic (MeSH) ; HEK293 Cells (MeSH) ; Humans (MeSH) ; Immunotherapy, Adoptive (MeSH) ; Interferon-gamma: genetics (MeSH) ; Interferon-gamma: pharmacology (MeSH) ; Kinetics (MeSH) ; Mice, Inbred NOD (MeSH) ; NF-kappa B: genetics (MeSH) ; Promoter Regions, Genetic (MeSH) ; Proof of Concept Study (MeSH) ; Receptors, Chimeric Antigen: genetics (MeSH) ; Receptors, Chimeric Antigen: metabolism (MeSH) ; T-Lymphocytes: immunology (MeSH) ; T-Lymphocytes: metabolism (MeSH) ; T-Lymphocytes: transplantation (MeSH) ; Tumor Hypoxia (MeSH) ; Tumor Microenvironment (MeSH) ; Tumor Necrosis Factor-alpha: genetics (MeSH) ; Tumor Necrosis Factor-alpha: pharmacology (MeSH) ; Xenograft Model Antitumor Assays (MeSH) ; Mice (MeSH) ; IFNG protein, human ; NF-kappa B ; Receptors, Chimeric Antigen ; TNF protein, human ; Tumor Necrosis Factor-alpha ; Interferon-gamma
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