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Preclinical development and selection of nanobody-based CAR-T cells targeting HER2-positive solid tumors

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Titel: Preclinical development and selection of nanobody-based CAR-T cells targeting HER2-positive solid tumors
Autoren: Fien Meeus, Arne Van der Vreken, Dorien Autaers, Timo W.M. De Groof, Arthur Esprit, Lorenzo Franceschini, Philippe Parone, Cleo Goyvaerts, Yannick De Vlaeminck, Nick Devoogdt, Karine Breckpot
Quelle: Molecular Therapy: Oncology, Vol 33, Iss 4, Pp 201088- (2025)
Verlagsinformationen: Elsevier, 2025.
Publikationsjahr: 2025
Bestand: LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Schlagwörter: MT: Regular Issue, Chimeric antigen receptors, HER2, nanobody, solid tumors, immunotherapy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Beschreibung: Chimeric antigen receptor (CAR)-T cell therapy revolutionized treatment of hematological malignancies, but translation to solid tumors remains difficult. Therefore, different avenues are explored to develop novel CAR-T cell products. Nanobodies have advantageous features for CAR design, such as ease of engineering and low immunogenicity, but predictive values on nanobody characteristics for optimal CAR-T cell function remain unclear. We performed a side-by-side evaluation of 12 nanobody-based (nano)CARs against human epidermal growth factor receptor 2 (HER2). All nanoCARs showed the ability to activate a reporter T cell line upon recognition of HER2pos cells. When evaluated in primary T cells, 6/12 nanoCARs showed the strongest reactivity and cytotoxicity against HER2pos glioblastoma and breast cancer cells. Moreover, only 1/12 was able to confer potent cytotoxicity against HER2pos melanoma cells. These data add to the current view that nanobody selection for CAR design remains subject to extensive side-by-side screening. Still, superior cytotoxicity across multiple solid tumor cell lines—determined using in vitro assays evaluating activation, cytokine secretion, and target cell-specific killing—led to selection and further characterization of a lead nanoCAR 1R59b, showing tumor control in an in vivo xenograft model, providing a promising HER2 nanoCAR for further (pre)clinical investigation.
Publikationsart: article
Dateibeschreibung: electronic resource
Sprache: English
ISSN: 2950-3299
Relation: http://www.sciencedirect.com/science/article/pii/S2950329925001572; https://doaj.org/toc/2950-3299
DOI: 10.1016/j.omton.2025.201088
Zugangs-URL: https://doaj.org/article/4539d37a10c44f1aa9f48740a989dd3f
Dokumentencode: edsdoj.4539d37a10c44f1aa9f48740a989dd3f
Datenbank: Directory of Open Access Journals
Beschreibung
Abstract:Chimeric antigen receptor (CAR)-T cell therapy revolutionized treatment of hematological malignancies, but translation to solid tumors remains difficult. Therefore, different avenues are explored to develop novel CAR-T cell products. Nanobodies have advantageous features for CAR design, such as ease of engineering and low immunogenicity, but predictive values on nanobody characteristics for optimal CAR-T cell function remain unclear. We performed a side-by-side evaluation of 12 nanobody-based (nano)CARs against human epidermal growth factor receptor 2 (HER2). All nanoCARs showed the ability to activate a reporter T cell line upon recognition of HER2pos cells. When evaluated in primary T cells, 6/12 nanoCARs showed the strongest reactivity and cytotoxicity against HER2pos glioblastoma and breast cancer cells. Moreover, only 1/12 was able to confer potent cytotoxicity against HER2pos melanoma cells. These data add to the current view that nanobody selection for CAR design remains subject to extensive side-by-side screening. Still, superior cytotoxicity across multiple solid tumor cell lines—determined using in vitro assays evaluating activation, cytokine secretion, and target cell-specific killing—led to selection and further characterization of a lead nanoCAR 1R59b, showing tumor control in an in vivo xenograft model, providing a promising HER2 nanoCAR for further (pre)clinical investigation.
ISSN:29503299
DOI:10.1016/j.omton.2025.201088