Szoor, Arpad and Toth, Gabor and Zsebik, Barbara and Szabo, Viktoria and Eshhar, Zelig and Abken, Hinrich and Vereb, Gyorgy (2020) Trastuzumab derived HER2-specific CARs for the treatment of trastuzumab-resistant breast cancer: CAR T cells penetrate and eradicate tumors that are not accessible to antibodies. CANCER LETTERS, 484. pp. 1-8. ISSN 0304-3835, 1872-7980
Full text not available from this repository. (Request a copy)Abstract
HER2-targeted monoclonal antibodies improve the outcome for advanced breast cancer patients; however, resistance to therapy is still frequent. Epitope masking and steric hindrance to antibody binding through matrix components are thought to be the major mechanism. We asked whether tumors resistant to trastuzumab can still be eliminated by CAR T cells redirected by the same antibody domain. While saturating doses of trastuzumab in the presence of CD16.176V.NK-92 effector cells and trastuzumab derived CAR T cells equally well recognized and killed HER2-positive tumor cells in a monolayer, only CAR T cells penetrated into the core region of tumor spheroids and exhibited cytotoxic activity in vitro, whereas antibodies failed. In NSG mice treatment with trastuzumab and CD16.176V.NK-92 cells only transiently retarded tumor growth but did not induce regression of clinically trastuzumab-resistant breast cancer xenografts. In contrast, one dose of HER2-specific CAR T cells eradicated established tumors resulting in long-term survival. Data indicate that CAR T cells can successfully combat antibody resistant tumors by targeting the same epitope suggesting that CAR T cells can penetrate the tumor matrix which is a barrier for antibodies.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CHIMERIC ANTIGEN RECEPTOR; DEPENDENT CELLULAR CYTOTOXICITY; HERCEPTIN-RESISTANT; IMMUNOTHERAPY; TRAFFICKING; XENOGRAFTS; ACTIVATION; PERTUZUMAB; JIMT-1; Breast cancer; HER2; Trastuzumab; Chimeric antigen receptor; Immunotherapy; Cell therapy; Tumor microenvironment; Extracellular matrix |
| 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: | 17 Mar 2021 12:43 |
| Last Modified: | 17 Mar 2021 12:43 |
| URI: | https://pred.uni-regensburg.de/id/eprint/44137 |
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