Soto, Karla E. G. and Loureiro, Liliana R. and Bartsch, Tabea and Arndt, Claudia and Kegler, Alexandra and Mitwasi, Nicola and Drewitz, Laura and Hoffmann, Lydia and Saleh, Haidy A. and Crespo, Eugenia and Mehnert, Maria and Daglar, Cansu and Abken, Hinrich and Momburg, Frank and Bachmann, Michael and Feldmann, Anja (2023) Targeting colorectal cancer cells using AND-gated adaptor RevCAR T-cells. FRONTIERS IN IMMUNOLOGY, 14: 1302354. ISSN 1664-3224,
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CARCINOEMBRYONIC ANTIGEN; SURFACE GLYCOPROTEIN; MR 34,000; B-CELL; EXPRESSION; THERAPY; EPCAM; CEA; UNICAR-T-CD123; CARCINOMA; colorectal cancer; CAR T-cells; AND-gate targeting; CEA; EpCAM |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Mar 2024 11:36 |
| Last Modified: | 23 Mar 2024 11:36 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60431 |
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