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In vivo dynamics and anti-tumor effects of EpCAM-directed CAR T-cells against brain metastases from lung cancer

Lung cancer patients are at risk for brain metastases and often succumb to their intracranial disease. Chimeric Antigen Receptor (CAR) T-cells emerged as a powerful cell-based immunotherapy for hematological malignancies; however, it remains unclear whether CAR T-cells represent a viable therapy for...

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Autores principales: Xu, Tao, Karschnia, Philipp, Cadilha, Bruno Loureiro, Dede, Sertac, Lorenz, Michael, Seewaldt, Niklas, Nikolaishvili, Elene, Müller, Katharina, Blobner, Jens, Teske, Nico, Herold, Julika J., Rejeski, Kai, Langer, Sigrid, Obeck, Hannah, Lorenzini, Theo, Mulazzani, Matthias, Zhang, Wenlong, Ishikawa-Ankerhold, Hellen, Buchholz, Veit R., Subklewe, Marion, Thon, Niklas, Straube, Andreas, Tonn, Joerg-Christian, Kobold, Sebastian, von Baumgarten, Louisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9851202/
https://www.ncbi.nlm.nih.gov/pubmed/36687005
http://dx.doi.org/10.1080/2162402X.2022.2163781
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author Xu, Tao
Karschnia, Philipp
Cadilha, Bruno Loureiro
Dede, Sertac
Lorenz, Michael
Seewaldt, Niklas
Nikolaishvili, Elene
Müller, Katharina
Blobner, Jens
Teske, Nico
Herold, Julika J.
Rejeski, Kai
Langer, Sigrid
Obeck, Hannah
Lorenzini, Theo
Mulazzani, Matthias
Zhang, Wenlong
Ishikawa-Ankerhold, Hellen
Buchholz, Veit R.
Subklewe, Marion
Thon, Niklas
Straube, Andreas
Tonn, Joerg-Christian
Kobold, Sebastian
von Baumgarten, Louisa
author_facet Xu, Tao
Karschnia, Philipp
Cadilha, Bruno Loureiro
Dede, Sertac
Lorenz, Michael
Seewaldt, Niklas
Nikolaishvili, Elene
Müller, Katharina
Blobner, Jens
Teske, Nico
Herold, Julika J.
Rejeski, Kai
Langer, Sigrid
Obeck, Hannah
Lorenzini, Theo
Mulazzani, Matthias
Zhang, Wenlong
Ishikawa-Ankerhold, Hellen
Buchholz, Veit R.
Subklewe, Marion
Thon, Niklas
Straube, Andreas
Tonn, Joerg-Christian
Kobold, Sebastian
von Baumgarten, Louisa
author_sort Xu, Tao
collection PubMed
description Lung cancer patients are at risk for brain metastases and often succumb to their intracranial disease. Chimeric Antigen Receptor (CAR) T-cells emerged as a powerful cell-based immunotherapy for hematological malignancies; however, it remains unclear whether CAR T-cells represent a viable therapy for brain metastases. Here, we established a syngeneic orthotopic cerebral metastasis model in mice by combining a chronic cranial window with repetitive intracerebral two-photon laser scanning-microscopy. This approach enabled in vivo-characterization of fluorescent CAR T-cells and tumor cells on a single-cell level over weeks. Intraparenchymal injection of Lewis lung carcinoma cells (expressing the tumor cell-antigen EpCAM) was performed, and EpCAM-directed CAR T-cells were injected either intravenously or into the adjacent brain parenchyma. In mice receiving EpCAM-directed CAR T-cells intravenously, we neither observed substantial CAR T-cell accumulation within the tumor nor relevant anti-tumor effects. Local CAR T-cell injection, however, resulted in intratumoral CAR T-cell accumulation compared to controls treated with T-cells lacking a CAR. This finding was accompanied by reduced tumorous growth as determined per in vivo-microscopy and immunofluorescence of excised brains and also translated into prolonged survival. However, the intratumoral number of EpCAM-directed CAR T-cells decreased during the observation period, pointing toward insufficient persistence. No CNS-specific or systemic toxicities of EpCAM-directed CAR T-cells were observed in our fully immunocompetent model. Collectively, our findings indicate that locally (but not intravenously) injected CAR T-cells may safely induce relevant anti-tumor effects in brain metastases from lung cancer. Strategies improving the intratumoral CAR T-cell persistence may further boost the therapeutic success.
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spelling pubmed-98512022023-01-20 In vivo dynamics and anti-tumor effects of EpCAM-directed CAR T-cells against brain metastases from lung cancer Xu, Tao Karschnia, Philipp Cadilha, Bruno Loureiro Dede, Sertac Lorenz, Michael Seewaldt, Niklas Nikolaishvili, Elene Müller, Katharina Blobner, Jens Teske, Nico Herold, Julika J. Rejeski, Kai Langer, Sigrid Obeck, Hannah Lorenzini, Theo Mulazzani, Matthias Zhang, Wenlong Ishikawa-Ankerhold, Hellen Buchholz, Veit R. Subklewe, Marion Thon, Niklas Straube, Andreas Tonn, Joerg-Christian Kobold, Sebastian von Baumgarten, Louisa Oncoimmunology Original Research Lung cancer patients are at risk for brain metastases and often succumb to their intracranial disease. Chimeric Antigen Receptor (CAR) T-cells emerged as a powerful cell-based immunotherapy for hematological malignancies; however, it remains unclear whether CAR T-cells represent a viable therapy for brain metastases. Here, we established a syngeneic orthotopic cerebral metastasis model in mice by combining a chronic cranial window with repetitive intracerebral two-photon laser scanning-microscopy. This approach enabled in vivo-characterization of fluorescent CAR T-cells and tumor cells on a single-cell level over weeks. Intraparenchymal injection of Lewis lung carcinoma cells (expressing the tumor cell-antigen EpCAM) was performed, and EpCAM-directed CAR T-cells were injected either intravenously or into the adjacent brain parenchyma. In mice receiving EpCAM-directed CAR T-cells intravenously, we neither observed substantial CAR T-cell accumulation within the tumor nor relevant anti-tumor effects. Local CAR T-cell injection, however, resulted in intratumoral CAR T-cell accumulation compared to controls treated with T-cells lacking a CAR. This finding was accompanied by reduced tumorous growth as determined per in vivo-microscopy and immunofluorescence of excised brains and also translated into prolonged survival. However, the intratumoral number of EpCAM-directed CAR T-cells decreased during the observation period, pointing toward insufficient persistence. No CNS-specific or systemic toxicities of EpCAM-directed CAR T-cells were observed in our fully immunocompetent model. Collectively, our findings indicate that locally (but not intravenously) injected CAR T-cells may safely induce relevant anti-tumor effects in brain metastases from lung cancer. Strategies improving the intratumoral CAR T-cell persistence may further boost the therapeutic success. Taylor & Francis 2023-01-13 /pmc/articles/PMC9851202/ /pubmed/36687005 http://dx.doi.org/10.1080/2162402X.2022.2163781 Text en © 2023 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Research
Xu, Tao
Karschnia, Philipp
Cadilha, Bruno Loureiro
Dede, Sertac
Lorenz, Michael
Seewaldt, Niklas
Nikolaishvili, Elene
Müller, Katharina
Blobner, Jens
Teske, Nico
Herold, Julika J.
Rejeski, Kai
Langer, Sigrid
Obeck, Hannah
Lorenzini, Theo
Mulazzani, Matthias
Zhang, Wenlong
Ishikawa-Ankerhold, Hellen
Buchholz, Veit R.
Subklewe, Marion
Thon, Niklas
Straube, Andreas
Tonn, Joerg-Christian
Kobold, Sebastian
von Baumgarten, Louisa
In vivo dynamics and anti-tumor effects of EpCAM-directed CAR T-cells against brain metastases from lung cancer
title In vivo dynamics and anti-tumor effects of EpCAM-directed CAR T-cells against brain metastases from lung cancer
title_full In vivo dynamics and anti-tumor effects of EpCAM-directed CAR T-cells against brain metastases from lung cancer
title_fullStr In vivo dynamics and anti-tumor effects of EpCAM-directed CAR T-cells against brain metastases from lung cancer
title_full_unstemmed In vivo dynamics and anti-tumor effects of EpCAM-directed CAR T-cells against brain metastases from lung cancer
title_short In vivo dynamics and anti-tumor effects of EpCAM-directed CAR T-cells against brain metastases from lung cancer
title_sort in vivo dynamics and anti-tumor effects of epcam-directed car t-cells against brain metastases from lung cancer
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9851202/
https://www.ncbi.nlm.nih.gov/pubmed/36687005
http://dx.doi.org/10.1080/2162402X.2022.2163781
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