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| Home > Publications database > Targeting CD276 with Adapter-CAR T-cells provides a novel therapeutic strategy in small cell lung cancer and prevents CD276-dependent fratricide. |
| Home > Publications database > Targeting CD276 with Adapter-CAR T-cells provides a novel therapeutic strategy in small cell lung cancer and prevents CD276-dependent fratricide. |
| Journal Article | DKFZ-2025-01573 |
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2025
Biomed Central
London
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Please use a persistent id in citations: doi:10.1186/s13045-025-01729-8
Abstract: Survival rates in Small Cell Lung Cancer (SCLC) remain dismal, posing a huge medical need for novel therapies. T-cells, engineered to express chimeric antigen receptors (CAR-T) have demonstrated clinical activity against a variety of haematological malignancies. Yet, efficacy against solid tumour entities remains limited.In this study, we investigated the expression of CD276 (B7-H3), an immune checkpoint molecule and promising target antigen for CAR-T therapy in SCLC, at the RNA and protein level. We further developed novel Fab-based adapter molecules (AM) targeting CD276 and optimized our previously established modular Adapter CAR-T (AdCAR-T) platform as well as AM dosing schemes.CD276 is broadly expressed across SCLC subtypes, representing a promising target for CAR-T therapy. We describe that T-cell activation and CAR-signalling induces CD276-expression on CAR-T, resulting in CD276-dependent fratricide, limiting anti-CD276-CAR-T expansion and activity. The AdCAR-T platform allows CAR-T expansion in absence of CD276 targeting. Novel CD276 targeted AMs demonstrate potent in vitro and in vivo activity against SCLC. Intermittent AM-dosing allows functional persistence of AdCAR-T in vivo in contrast to CD276-targeted conventional CAR-T. AdCAR-T in vivo expansion and activity is further promoted by introducing activation-induced, AM remote controlled, IL-18 secretion into the AdCAR-T design.We identified CD276 as a promising target antigen, uniformly expressed in SCLC and demonstrate the therapeutic potential of novel anti-CD276 Fab-based AM in combination with optimized, IL-18 armoured AdCAR-T.
Keyword(s): Humans (MeSH) ; Small Cell Lung Carcinoma: therapy (MeSH) ; Small Cell Lung Carcinoma: immunology (MeSH) ; Lung Neoplasms: therapy (MeSH) ; Lung Neoplasms: immunology (MeSH) ; Immunotherapy, Adoptive: methods (MeSH) ; Animals (MeSH) ; Receptors, Chimeric Antigen: immunology (MeSH) ; Mice (MeSH) ; B7 Antigens: immunology (MeSH) ; B7 Antigens: metabolism (MeSH) ; T-Lymphocytes: immunology (MeSH) ; Cell Line, Tumor (MeSH) ; AdCAR-T ; CD276 ; Fab-based adapter molecule ; Fratricide ; Immunotherapy ; In vivo solid tumor targeting ; SCLC ; Receptors, Chimeric Antigen ; B7 Antigens ; CD276 protein, human
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