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Cited by 24CAR-T cell therapy researchImmunotherapy and Immune ResponsesCRISPR and Genetic Engineering

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

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Harrer, Dennis Christoph, Schenkel, Charlotte, Bezler, Valerie, Kaljanac, Marcell, Hartley, Jordan, Barden, Markus, Pan, Hong, Holzinger, Astrid +2 more·2022·Cells
DOI 10.3390/cells11233839PMC PMC9737386
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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, 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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Cited by

Sorted by citations

Authors
Harrer, D. C., Schenkel, C., Bezler, V., Kaljanac, M., Hartley, J., Barden, M., Pan, H., Holzinger, A., Herr, W., & Abken, H.
Affiliations
  • University Hospital Regensburg (DE)
  • Leibniz Institute for Immunotherapy (DE)
Corresponding author
Harrer, Dennis Christoph
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2022-11-30
Volume
11
Issue
23
Pages
3839
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells11233839
PMC
PMC9737386
OpenAlex
W4311001952
Cited by
24
References
0
Citations by year
2026: 10 · 2025: 5 · 2024: 7 · 2023: 2
FWCI
1.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • University of Regensburg Publication Server (University of Regensburg)
Funders
  • Deutsche Forschungsgemeinschaft (324392634-TRR221)
  • Else-Kröner Fresenius Foundation (324392634-TRR221)
  • university of Regensburg intramural (324392634-TRR221)
Topics
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
Keywords
chimeric antigen receptor T cells, type I interferon, trucks, T cell exhaustion, anticancer activity, CAR T cell persistence
MeSH terms
Carcinoma, Humans, Interferon Type I, Receptors, Antigen, T-Cell, T-Lymphocytes, Cytokines

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