TY  - JOUR
AU  - Soto, Karla E G
AU  - Loureiro, Liliana R
AU  - Bartsch, Tabea
AU  - Arndt, Claudia
AU  - Kegler, Alexandra
AU  - Mitwasi, Nicola
AU  - Drewitz, Laura
AU  - Hoffmann, Lydia
AU  - Saleh, Haidy A
AU  - Crespo, Eugenia
AU  - Mehnert, Maria
AU  - Daglar, Cansu
AU  - Abken, Hinrich
AU  - Momburg, Frank
AU  - Bachmann, Michael
AU  - Feldmann, Anja
TI  - Targeting colorectal cancer cells using AND-gated adaptor RevCAR T-cells.
JO  - Frontiers in immunology
VL  - 14
SN  - 1664-3224
CY  - Lausanne
PB  - Frontiers Media
M1  - DKFZ-2024-00024
SP  - 1302354
PY  - 2023
AB  - Despite the success of chimeric antigen receptor (CAR) T-cells especially for treating hematological malignancies, critical drawbacks, such as 'on-target, off-tumor' toxicities, need to be addressed to improve safety in translating to clinical application. This is especially true, when targeting tumor-associated antigens (TAAs) that are not exclusively expressed by solid tumors but also on hea9lthy tissues. To improve the safety profile, we developed switchable adaptor CAR systems including the RevCAR system. RevCAR T-cells are activated by cross-linking of bifunctional adaptor molecules termed target modules (RevTM). In a further development, we established a Dual-RevCAR system for an AND-gated combinatorial targeting by splitting the stimulatory and co-stimulatory signals of the RevCAR T-cells on two individual CARs. Examples of common markers for colorectal cancer (CRC) are the carcinoembryonic antigen (CEA) and the epithelial cell adhesion molecule (EpCAM), while these antigens are also expressed by healthy cells. Here we describe four novel structurally different RevTMs for targeting of CEA and EpCAM. All anti-CEA and anti-EpCAM RevTMs were validated and the simultaneous targeting of CEA+ and EpCAM+ cancer cells redirected specific in vitro and in vivo killing by Dual-RevCAR T-cells. In summary, we describe the development of CEA and EpCAM specific adaptor RevTMs for monospecific and AND-gated targeting of CRC cells via the RevCAR platform as an improved approach to increase tumor specificity and safety of CAR T-cell therapies.
KW  - AND-gate targeting (Other)
KW  - CAR T-cells (Other)
KW  - CEA (Other)
KW  - EpCAM (Other)
KW  - colorectal cancer (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:38169746
C2  - pmc:PMC10758449
DO  - DOI:10.3389/fimmu.2023.1302354
UR  - https://inrepo02.dkfz.de/record/286660
ER  -