| Autor: |
Stijn De Munter, Juliane Buhl, Laurenz De Cock, Alexander Van Parys, Willem Daneels, Eva Pascal, Lucas Deseins, Joline Ingels, Glenn Goetgeluk, Lore Billiet, Melissa Pille, Niels Vandamme, Jo Van Dorpe, Fritz Offner, Erik Depla, Jan Tavernier, Tessa Kerre, Jarno Drost, Bart Vandekerckhove |
| Rok vydání: |
2023 |
| Popis: |
CD70 is an attractive target for chimeric antigen receptor (CAR) T cell therapy as treatment for both solid and liquid malignancies. However, functionality of CD70-specific CARs is only modest. Here, we optimized a CD70-specific VHH based CAR (nanoCAR). We evaluated the nanoCARs in clinically relevant modelsin vitro, using co-cultures of CD70-specific nanoCAR T cells with malignant rhabdoid tumor organoids, andin vivoby using a diffuse large B cell lymphoma (DLBCL) patient-derived xenograft (PDX) model. Whereas the nanoCAR T cells were highly efficient in organoid co-cultures, they showed only modest efficacy in the PDX model. Knocking out CD70 expression by the nanoCAR T cells resulted in dramatically enhanced functionality in the PDX model, suggesting that endogenous CD70 interaction with the nanoCAR induces exhaustion. Through single-cell transcriptomics, we obtained evidence that CD70KO CD70-specific nanoCAR T cells are protected from antigen induced exhaustion. Our data shows that CARs targeted to endogenous T cell antigens, negatively affect CAR T cell functionality by inducing an exhausted state which can be overcome by knocking out the specific target, in this case CD70. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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