Harrer, Dennis Christoph and Schenkel, Charlotte and Bezler, Valerie and Kaljanac, Marcell and Hartley, Jordan and Barden, Markus and Pan, Hong and Holzinger, Astrid and Herr, Wolfgang and Abken, Hinrich (2022) CAR Triggered Release of Type-1 Interferon Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop. CELLS, 11 (23): 3839. ISSN , 2073-4409
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CHIMERIC ANTIGEN RECEPTORS; CANCER; COSTIMULATION; GENERATION; CYTOKINE; PROTEIN; TRUCKS; CAR T-cells; TRUCK; inducible; negative feedback |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Immunologie Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 13 Feb 2024 06:52 |
| Last Modified: | 13 Feb 2024 06:52 |
| URI: | https://pred.uni-regensburg.de/id/eprint/56569 |
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