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CAR T cells as micropharmacies against solid cancers: Combining effector T-cell mediated cell death with vascular targeting in a one-step engineering process
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 ti...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group US
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10581901/ https://www.ncbi.nlm.nih.gov/pubmed/37391502 http://dx.doi.org/10.1038/s41417-023-00642-x |
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author | 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 |
author_facet | 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 |
author_sort | Altvater, Bianca |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10581901 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
spelling | pubmed-105819012023-10-19 CAR T cells as micropharmacies against solid cancers: Combining effector T-cell mediated cell death with vascular targeting in a one-step engineering process 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 Cancer Gene Ther Article 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. Nature Publishing Group US 2023-06-30 2023 /pmc/articles/PMC10581901/ /pubmed/37391502 http://dx.doi.org/10.1038/s41417-023-00642-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article 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 CAR T cells as micropharmacies against solid cancers: Combining effector T-cell mediated cell death with vascular targeting in a one-step engineering process |
title | CAR T cells as micropharmacies against solid cancers: Combining effector T-cell mediated cell death with vascular targeting in a one-step engineering process |
title_full | CAR T cells as micropharmacies against solid cancers: Combining effector T-cell mediated cell death with vascular targeting in a one-step engineering process |
title_fullStr | CAR T cells as micropharmacies against solid cancers: Combining effector T-cell mediated cell death with vascular targeting in a one-step engineering process |
title_full_unstemmed | CAR T cells as micropharmacies against solid cancers: Combining effector T-cell mediated cell death with vascular targeting in a one-step engineering process |
title_short | CAR T cells as micropharmacies against solid cancers: Combining effector T-cell mediated cell death with vascular targeting in a one-step engineering process |
title_sort | car t cells as micropharmacies against solid cancers: combining effector t-cell mediated cell death with vascular targeting in a one-step engineering process |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10581901/ https://www.ncbi.nlm.nih.gov/pubmed/37391502 http://dx.doi.org/10.1038/s41417-023-00642-x |
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