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

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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Main Authors: Tao Xu, Philipp Karschnia, Bruno Loureiro Cadilha, Sertac Dede, Michael Lorenz, Niklas Seewaldt, Elene Nikolaishvili, Katharina Müller, Jens Blobner, Nico Teske, Julika J. Herold, Kai Rejeski, Sigrid Langer, Hannah Obeck, Theo Lorenzini, Matthias Mulazzani, Wenlong Zhang, Hellen Ishikawa-Ankerhold, Veit R. Buchholz, Marion Subklewe, Niklas Thon, Andreas Straube, Joerg-Christian Tonn, Sebastian Kobold, Louisa von Baumgarten
Format: Article
Language:English
Published: Taylor & Francis Group 2023-12-01
Series:OncoImmunology
Subjects:
CAR T-cells
adoptive immunotherapy
brain metastasis
CNS tumor
lung cancer
in vivo microscopy
Online Access:https://www.tandfonline.com/doi/10.1080/2162402X.2022.2163781
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Summary: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.
ISSN:2162-402X

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