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

Xu, T; Karschnia, P; Cadilha, BL; Dede, S; Lorenz, M; Seewaldt, N; Nikolaishvili, E; M&#252;ller, K; Blobner, J; Teske, N; Herold, JJ; Rejeski, K; Langer, S; Obeck, H; Lorenzini, T; Mulazzani, M; Zhang, W; Ishikawa-Ankerhold, H; Buchholz, VR; Subklewe, M; Thon, N; Straube, A; Tonn, JC; Kobold, S; von Baumgarten, L

Author(s): Xu, T; Karschnia, P; Cadilha, BL; Dede, S; Lorenz, M; Seewaldt, N; Nikolaishvili, E; Müller, K; Blobner, J; Teske, N; Herold, JJ; Rejeski, K; Langer, S; Obeck, H; Lorenzini, T; Mulazzani, M; Zhang, W; Ishikawa-Ankerhold, H; Buchholz, VR; Subklewe, M; Thon, N; Straube, A; Tonn, JC; Kobold, S; von Baumgarten, L;
Details: Publication Year 2023,Volume 12,Issue #1,Page 2163781
Journal Title: OncoImmunology
Abstract: 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.
Publisher: Taylor & Frances
Keywords: Mice; Animals; Epithelial Cell Adhesion Molecule; Receptors, Antigen, T-Cell; Immunotherapy, Adoptive/methods; Cytotoxicity, Immunologic; T-Lymphocytes; *Lung Neoplasms/therapy; *Brain Neoplasms/therapy; Antigens, Neoplasm; CAR T-cells; CNS tumor; adoptive immunotherapy; brain metastasis; histology; in vivo microscopy; lung cancer; survival
Research Division(s): Immunology
PubMed ID: 36687005
Publisher's Version: https://doi.org/10.1080/2162402x.2022.2163781
Open Access at Publisher's Site: https://doi.org/10.1080/2162402X.2022.2163781
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-03-17 11:09:20

Last Modified: 2023-03-17 11:19:43