PT  - JOURNAL ARTICLE
AU  - Stijn De Munter
AU  - Juliane Buhl
AU  - Laurenz De Cock
AU  - Alexander Van Parys
AU  - Willem Daneels
AU  - Eva Pascal
AU  - Lucas Deseins
AU  - Joline Ingels
AU  - Glenn Goetgeluk
AU  - Lore Billiet
AU  - Melissa Pille
AU  - Niels Vandamme
AU  - Jo Van Dorpe
AU  - Fritz Offner
AU  - Erik Depla
AU  - Jan Tavernier
AU  - Tessa Kerre
AU  - Jarno Drost
AU  - Bart Vandekerckhove
TI  - Knocking out CD70 rescues CD70-specific nanoCAR T cells from antigen induced exhaustion
AID  - 10.1101/2023.01.22.523482
DP  - 2023 Jan 01
TA  - bioRxiv
PG  - 2023.01.22.523482
4099  - http://biorxiv.org/content/early/2023/01/22/2023.01.22.523482.short
4100  - http://biorxiv.org/content/early/2023/01/22/2023.01.22.523482.full
AB  - 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 models in vitro, using co-cultures of CD70-specific nanoCAR T cells with malignant rhabdoid tumor organoids, and in vivo by 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.Competing Interest StatementAVP, ED, JT are affiliated with Orionis Biosciences BV (as a scientific advisor and/or an employee) and holds equity interests in the Company. JT received financial research support from Orionis Biosciences BV. All the other authors declare no conflict of interest.