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CAR Triggered Release of Type-1 Interferon Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop

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...

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Autores principales: Harrer, Dennis Christoph, Schenkel, Charlotte, Bezler, Valerie, Kaljanac, Marcell, Hartley, Jordan, Barden, Markus, Pan, Hong, Holzinger, Astrid, Herr, Wolfgang, Abken, Hinrich
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9737386/
https://www.ncbi.nlm.nih.gov/pubmed/36497099
http://dx.doi.org/10.3390/cells11233839
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author Harrer, Dennis Christoph
Schenkel, Charlotte
Bezler, Valerie
Kaljanac, Marcell
Hartley, Jordan
Barden, Markus
Pan, Hong
Holzinger, Astrid
Herr, Wolfgang
Abken, Hinrich
author_facet Harrer, Dennis Christoph
Schenkel, Charlotte
Bezler, Valerie
Kaljanac, Marcell
Hartley, Jordan
Barden, Markus
Pan, Hong
Holzinger, Astrid
Herr, Wolfgang
Abken, Hinrich
author_sort Harrer, Dennis Christoph
collection PubMed
description 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, IFNα and IFNβ 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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spelling pubmed-97373862022-12-11 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 Abken, Hinrich Cells Article 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, IFNα and IFNβ 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. MDPI 2022-11-30 /pmc/articles/PMC9737386/ /pubmed/36497099 http://dx.doi.org/10.3390/cells11233839 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
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
title CAR Triggered Release of Type-1 Interferon Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop
title_full CAR Triggered Release of Type-1 Interferon Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop
title_fullStr CAR Triggered Release of Type-1 Interferon Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop
title_full_unstemmed CAR Triggered Release of Type-1 Interferon Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop
title_short CAR Triggered Release of Type-1 Interferon Limits CAR T-Cell Activities by an Artificial Negative Autocrine Loop
title_sort car triggered release of type-1 interferon limits car t-cell activities by an artificial negative autocrine loop
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9737386/
https://www.ncbi.nlm.nih.gov/pubmed/36497099
http://dx.doi.org/10.3390/cells11233839
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