Kath, Jonas and Franke, Clemens and Drosdek, Vanessa and Du, Weijie and Glaser, Viktor and Fuster-Garcia, Carla and Stein, Maik and Zittel, Tatiana and Schulenberg, Sarah and Porter, Caroline E. and Andersch, Lena and Kuenkele, Annette and Alcaniz, Joshua and Hoffmann, Jens and Abken, Hinrich and Abou-el-Enein, Mohamed and Pruss, Axel and Suzuki, Masataka and Cathomen, Toni and Stripecke, Renata and Volk, Hans-Dieter and Reinke, Petra and Schmueck-Henneresse, Michael and Wagner, Dimitrios L. (2024) Integration of ζ-deficient CARs into the CD3ζ gene conveys potent cytotoxicity in T and NK cells. BLOOD, 143 (25). pp. 2599-2611. ISSN 0006-4971, 1528-0020
Full text not available from this repository. (Request a copy)Abstract
Chimeric antigen receptor (CAR)-redirected immune cells hold significant fi cant therapeutic potential for oncology, autoimmune diseases, transplant medicine, and infections. All approved CAR-T therapies rely on personalized manufacturing using undirected viral gene transfer, which results in nonphysiological regulation of CAR-signaling and limits their accessibility due to logistical challenges, high costs and biosafety requirements. Random gene transfer modalities pose a risk of malignant transformation by insertional mutagenesis. Here, we propose a novel approach utilizing CRISPR-Cas gene editing to redirect T cells and natural killer (NK) cells with CARs. By transferring shorter, truncated CAR-transgenes lacking a main activation domain into the human CD3 (CD247) gene, functional CAR fusion-genes are generated that exploit the endogenous CD3 gene as the CAR's activation domain. Repurposing this T/NK-cell lineage gene facilitated physiological regulation of CAR expression and redirection of various immune cell types, including conventional T cells, TCR gamma/delta gamma / delta T cells, regulatory T cells, and NK cells. In T cells, CD3 in-frame fusion eliminated TCR surface expression, reducing the risk of graft-versus-host disease in allogeneic off-the- shelf settings. CD3 -CD19-CAR-T cells exhibited comparable leukemia control to TCRa a chain constant (TRAC)-replaced and lentivirus-transduced CAR-T cells in vivo. Tuning of CD3 -CAR-expression levels significantly fi cantly improved the in vivo efficacy. fi cacy. Notably, CD3 gene editing enabled redirection of NK cells without impairing their canonical functions. Thus, CD3 gene editing is a promising platform for the development of allogeneic off-the-shelf cell therapies using redirected killer lymphocytes.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CHIMERIC-ANTIGEN-RECEPTOR; GENOMIC DNA; EXPRESSION; THERAPY; BASE; IMMUNOTHERAPY; SURFACE; LOCUS; CHAIN |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Immunologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 22 Jan 2026 07:28 |
| Last Modified: | 22 Jan 2026 07:28 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65411 |
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