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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2023
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.
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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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