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CAR Triggered Release of Type-1 Interferon Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop
Harrer, Dennis Christoph
, Schenkel, Charlotte, Bezler, Valerie, Kaljanac, Marcell, Hartley, Jordan, Barden, Markus, Pan, Hong, Holzinger, Astrid, Herr, Wolfgang und Abken, Hinrich
(2022)
CAR Triggered Release of Type-1 Interferon Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop.
Cells 11 (23), S. 3839.
Veröffentlichungsdatum dieses Volltextes: 14 Dez 2022 13:09
Artikel
DOI zum Zitieren dieses Dokuments: 10.5283/epub.53413
Zusammenfassung
The advent of chimeric antigen receptor (CAR) T cells expedited the field of cancer immunotherapy enabling durable remissions in patients with refractory hematological malignancies. T cells redirected for universal cytokine-mediated killing (TRUCKs), commonly referred to as "fourth generation" CAR T-cells, are designed to release engineered payloads upon CAR-induced T-cell activation. Building on ...
The advent of chimeric antigen receptor (CAR) T cells expedited the field of cancer immunotherapy enabling durable remissions in patients with refractory hematological malignancies. T cells redirected for universal cytokine-mediated killing (TRUCKs), commonly referred to as "fourth generation" CAR T-cells, are designed to release engineered payloads upon CAR-induced T-cell activation. Building on the TRUCK technology, we aimed to generate CAR T-cells with a CAR-inducible artificial, self-limiting autocrine loop. To this end, we engineered CAR T-cells with CAR triggered secretion of type-1 interferons (IFNs). At baseline, IFN alpha and IFN beta CAR T-cells showed similar capacities in cytotoxicity and cytokine secretion compared to conventional CAR T-cells. However, under "stress" conditions of repetitive rounds of antigen stimulation using BxPC-3 pancreas carcinoma cells as targets, anti-tumor activity faded in later rounds while being fully active in destructing carcinoma cells during first rounds of stimulation. Mechanistically, the decline in activity was primarily based on type-1 IFN augmented CAR T-cell apoptosis, which was far less the case for CAR T-cells without IFN release. Such autocrine self-limiting loops can be used for applications where transient CAR T-cell activity and persistence upon target recognition is desired to avoid lasting toxicities.
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| Dokumentenart | Artikel | ||||
| Titel eines Journals oder einer Zeitschrift | Cells | ||||
| Verlag: | MDPI | ||||
|---|---|---|---|---|---|
| Ort der Veröffentlichung: | BASEL | ||||
| Band: | 11 | ||||
| Nummer des Zeitschriftenheftes oder des Kapitels: | 23 | ||||
| Seitenbereich: | S. 3839 | ||||
| Datum | 30 November 2022 | ||||
| Institutionen | Medizin > Lehrstuhl für Immunologie Medizin > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) | ||||
| Identifikationsnummer |
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| Stichwörter / Keywords | CHIMERIC ANTIGEN RECEPTORS; CANCER; COSTIMULATION; GENERATION; CYTOKINE; PROTEIN; TRUCKS; CAR T-cells; TRUCK; inducible; negative feedback | ||||
| Dewey-Dezimal-Klassifikation | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin | ||||
| Status | Veröffentlicht | ||||
| Begutachtet | Ja, diese Version wurde begutachtet | ||||
| An der Universität Regensburg entstanden | Ja | ||||
| URN der UB Regensburg | urn:nbn:de:bvb:355-epub-534131 | ||||
| Dokumenten-ID | 53413 |
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