Fourth generation Glypican-3–specific CAR-NK cells co-secreting IL-15 and IFN-α have increased anti-tumor function versus hepatocellular carcinoma

نویسندگان

چکیده

Abstract Hepatocellular carcinoma (HCC) ranks as the third most frequent cause of cancer-related mortality, indicating urgent need for effective therapies. Glypican-3 (GPC3) is up-regulated in HCC and not expressed normal liver cells, representing a strategic target. Chimeric antigen receptor (CAR)-modified natural killer (NK) cells are promising immunotherapeutic approach cancer treatment. However, their potential applications have been fully explored HCC. We patented protocol purification expansion clinically relevant numbers NK starting from perfusate deceased donors. Further, we demonstrated that activating with interferon-alpha (IFN-α) potentiates immune response vitro vivo both murine model hepatocarcinoma viral hepatitis. In this study, engineered primary CAR-NK to acquire specificity GPC3. The construct consists intracellular signaling region CD28, 4–1BB, CD3ζ CD8α hinge domain truncated form human epidermal growth factor (tEGFR) suicide gene. fourth-generation designed secrete transgenic cytokine IL-15, essential function survival. A second plasmid was also generated differing additional secretion IFN-α. Here show could achieve transduction efficiency above 50%. Exposure GPC3+ resulted enhanced specific cytotoxicity production such al IL-2 IFN-γ; moreover IFN-α significantly increased anti-GPC3 function. Our data encourage preclinical proof-of-concept studies translate GPC3-specific treatment option patients. This work supported by Fondazione Ri.MED (Fondo Generale, ID 10019) ISMETT (ATMP-P A105412 project, I00000219).

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ژورنال

عنوان ژورنال: Journal of Immunology

سال: 2023

ISSN: ['1550-6606', '0022-1767']

DOI: https://doi.org/10.4049/jimmunol.210.supp.146.07