Academic Journal
CAR T cells as micropharmacies against solid cancers: Combining effector T-cell mediated cell death with vascular targeting in a one-step engineering process
| العنوان: | CAR T cells as micropharmacies against solid cancers: Combining effector T-cell mediated cell death with vascular targeting in a one-step engineering process |
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| المؤلفون: | Altvater, Bianca, Kailayangiri, Sareetha, Spurny, Christian, Flügge, Maike, Meltzer, Jutta, Greune, Lea, Urban, Katja, Schwöppe, Christian, Brand, Caroline, Schliemann, Christoph, Hintelmann, Heike, Harrach, Saliha, Hartmann, Wolfgang, Abken, Hinrich, Kuehle, Johannes, Schambach, Axel, Görlich, Dennis, Berdel, Wolfgang E., Rossig, Claudia |
| المساهمون: | Deutsche Forschungsgemeinschaft |
| المصدر: | Cancer Gene Therapy ; volume 30, issue 10, page 1355-1368 ; ISSN 0929-1903 1476-5500 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2023 |
| الوصف: | To enhance the potency of chimeric antigen receptor (CAR) engineered T cells in solid cancers, we designed a novel cell-based combination strategy with an additional therapeutic mode of action. CAR T cells are used as micropharmacies to produce a targeted pro-coagulatory fusion protein, truncated tissue factor (tTF)-NGR, which exerts pro-coagulatory activity and hypoxia upon relocalization to the vascular endothelial cells that invade tumor tissues. Delivery by CAR T cells aimed to induce locoregional tumor vascular infarction for combined immune-mediated and hypoxic tumor cell death. Human T cells that were one-vector gene-modified to express a G D2 -specific CAR along with CAR-inducible tTF-NGR exerted potent G D2 -specific effector functions while secreting tTF-NGR that activates the extrinsic coagulation pathway in a strictly G D2 -dependent manner. In murine models, the CAR T cells infiltrated G D2 -positive tumor xenografts, secreted tTF-NGR into the tumor microenvironment and showed a trend towards superior therapeutic activity compared with control cells producing functionally inactive tTF-NGR. In vitro evidence supports a mechanism of hypoxia-mediated enhancement of T cell cytolytic activity. We conclude that combined CAR T cell targeting with an additional mechanism of antitumor action in a one-vector engineering strategy is a promising approach to be further developed for targeted treatment of solid cancers. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/s41417-023-00642-x |
| الاتاحة: | http://dx.doi.org/10.1038/s41417-023-00642-x https://www.nature.com/articles/s41417-023-00642-x.pdf https://www.nature.com/articles/s41417-023-00642-x |
| Rights: | https://creativecommons.org/licenses/by/4.0 ; https://creativecommons.org/licenses/by/4.0 |
| رقم الانضمام: | edsbas.90E0B72A |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41417-023-00642-x |
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