Altvater, Bianca and Kailayangiri, Sareetha and Spurny, Christian and Fluegge, Maike and Meltzer, Jutta and Greune, Lea and Urban, Katja and Schwoeppe, Christian and Brand, Caroline and Schliemann, Christoph and Hintelmann, Heike and Harrach, Saliha and Hartmann, Wolfgang and Abken, Hinrich and Kuehle, Johannes and Schambach, Axel and Goerlich, Dennis and Berdel, Wolfgang E. and Rossig, Claudia (2023) CAR T cells as micropharmacies against solid cancers: Combining effector T-cell mediated cell death with vascular targeting in a one-step engineering process. CANCER GENE THERAPY, 30 (10). pp. 1355-1368. ISSN 0929-1903, 1476-5500
Full text not available from this repository. (Request a copy)Abstract
To enhance the potency of chimeric antigen receptor (CAR) engineered T cells in solid cancers, we designed a novel cell-based combination strategy with an additional therapeutic mode of action. CAR T cells are used as micropharmacies to produce a targeted pro-coagulatory fusion protein, truncated tissue factor (tTF)-NGR, which exerts pro-coagulatory activity and hypoxia upon relocalization to the vascular endothelial cells that invade tumor tissues. Delivery by CAR T cells aimed to induce locoregional tumor vascular infarction for combined immune-mediated and hypoxic tumor cell death. Human T cells that were one-vector gene-modified to express a G(D2)-specific CAR along with CAR-inducible tTF-NGR exerted potent G(D2)-specific effector functions while secreting tTF-NGR that activates the extrinsic coagulation pathway in a strictly G(D2)-dependent manner. In murine models, the CAR T cells infiltrated G(D2)-positive tumor xenografts, secreted tTF-NGR into the tumor microenvironment and showed a trend towards superior therapeutic activity compared with control cells producing functionally inactive tTF-NGR. In vitro evidence supports a mechanism of hypoxia-mediated enhancement of T cell cytolytic activity. We conclude that combined CAR T cell targeting with an additional mechanism of antitumor action in a one-vector engineering strategy is a promising approach to be further developed for targeted treatment of solid cancers.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TUMOR-VESSEL INFARCTION; TISSUE-FACTOR; ANTITUMOR-ACTIVITY; ANTICANCER THERAPY; EWING SARCOMA; IN-VIVO; LYMPHOCYTES; PERSISTENCE; ACTIVATION; RECEPTORS; |
| 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 13:33 |
| Last Modified: | 23 Mar 2024 13:33 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60503 |
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