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Harrer, Dennis Christoph ; Schenkel, Charlotte ; Bezler, Valerie ; Kaljanac, Marcell ; Hartley, Jordan ; Barden, Markus ; Pan, Hong ; Holzinger, Astrid ; Herr, Wolfgang ; Abken, Hinrich

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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Details

DokumentenartArtikel
Titel eines Journals oder einer ZeitschriftCells
Verlag:MDPI
Ort der Veröffentlichung:BASEL
Band:11
Nummer des Zeitschriftenheftes oder des Kapitels:23
Seitenbereich:S. 3839
Datum30 November 2022
InstitutionenMedizin > Lehrstuhl für Immunologie
Medizin > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie)
Identifikationsnummer
WertTyp
10.3390/cells11233839DOI
Stichwörter / KeywordsCHIMERIC ANTIGEN RECEPTORS; CANCER; COSTIMULATION; GENERATION; CYTOKINE; PROTEIN; TRUCKS; CAR T-cells; TRUCK; inducible; negative feedback
Dewey-Dezimal-Klassifikation600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin
StatusVeröffentlicht
BegutachtetJa, diese Version wurde begutachtet
An der Universität Regensburg entstandenJa
URN der UB Regensburgurn:nbn:de:bvb:355-epub-534131
Dokumenten-ID53413

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