EXTH-02. ANTI-TUMOR EFFECTS AND IN VIVO DYNAMICS OF EPCAM-DIRECTED CAR T-CELLS FOR BRAIN METASTASES FROM LUNG CANCER. (14th November 2022)

• Record Type: Journal Article
• Authors: Xu, Tao; Karschnia, Philipp; Cadilha, Bruno; Dede, Sertac; Lorenz, Michael; Seewaldt, Niklas; Nikolaishvili, Elene; Müller, Katharina; Blobner, Jens; Teske, Nico; 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
• Is Part Of: Neuro-oncology. Volume 24(2022)Supplement 7
• Page Start: vii208
• Page End: vii209
• Publication Date: 2022-11-14
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noac209.801
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: BACKGROUND: Lung cancer patients are at a high risk for brain metastases, and affected patients frequently 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 therapeutic avenue for brain metastases. METHODS: A fully immunocompetent, orthotopic cerebral metastasis model was established in mice by combining a chronic cranial window with repetitive intracerebral two-photon laser scanning microscopy. This approach enabled the in vivo -characterization of fluorescent CAR T-cells and tumor cells on a single-cell level over weeks. Intraparenchymal injection of EpCAM-expressing Lewis lung carcinoma cells was performed, and EpCAM-directed CAR T-cells ( EpCAM CAR T-cells) were injected into the adjacent brain parenchyma after brain tumor formation. RESULTS: All mice had visible tumor take with rapidly growing lesions following intracranial tumor cell injection. In mice treated with EpCAM CAR T-cells, we observed substantial CAR T-cell accumulation within the tumor compared to controls treated with undirected T-cells. This was paralleled by lower velocities of EpCAM CAR T-cells, characterizing antitumor cytotoxicity due to 'immune cell'-'tumor cell' contacts. Consequently, treatment with EpCAM CAR T-cells resulted in reduced tumorous growth as determined per in vivo -microscopy (median tumor area on day 10: 1.8 versus 10.8 mm 2 ; p=0.001) and immunohistochemistry of excised brains. However, the number of intratumoral EpCAM CAR T-cells within the tumor markedly decreased during the observation period, pointing towards insufficient persistence. Accordingly, survival was prolonged in mice receiving EpCAM CAR T-cells but long-lasting remission was rare (median survival: 15 versus 13 days; p =0.012). No CNS-specific or systemic toxicities of EpCAMCAR T-cells were encountered. CONCLUSION: Our findings indicate that EpCAM CAR T-cells injected into the cerebral parenchyma may safely induce relevant anti-tumor effects in brain metastases from lung cancer. Strategies improving the CAR T-cell persistence within brain metastases are warranted to further boost the therapeutic success.