Rational design of PD-1-CD28 immunostimulatory fusion proteins for CAR T cell therapy
© 2023. The Author(s)..
BACKGROUND: In many situations, the therapeutic efficacy of CAR T cells is limited due to immune suppression and poor persistence. Immunostimulatory fusion protein (IFP) constructs have been advanced as a tool to convert suppressive signals into stimulation and thus promote the persistence of T cells, but no universal IFP design has been established so far. We now took advantage of a PD-1-CD28 IFP as a clinically relevant structure to define key determinants of IFP activity.
METHODS: We compared different PD-1-CD28 IFP variants in a human leukemia model to assess the impact of distinctive design choices on CAR T cell performance in vitro and a xenograft mouse model.
RESULTS: We observed that IFP constructs that putatively exceed the extracellular length of PD-1 induce T-cell response without CAR target recognition, rendering them unsuitable for tumour-specific therapy. IFP variants with physiological PD-1 length ameliorated CAR T cell effector function and proliferation in response to PD-L1+ tumour cells in vitro and prolonged survival in vivo. Transmembrane or extracellular CD28 domains were found to be replaceable by corresponding PD-1 domains for in vivo efficacy.
CONCLUSION: PD-1-CD28 IFP constructs must mimic the physiological interaction of PD-1 with PD-L1 to retain selectivity and mediate CAR-conditional therapeutic activity.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:129 |
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| Enthalten in: |
British journal of cancer - 129(2023), 4 vom: 04. Sept., Seite 696-705 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lorenzini, Theo [VerfasserIn] |
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| Links: |
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| Themen: |
B7-H1 Antigen |
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| Anmerkungen: |
Date Completed 14.08.2023 Date Revised 15.08.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41416-023-02332-9 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM359018750 |
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| 245 | 1 | 0 | |a Rational design of PD-1-CD28 immunostimulatory fusion proteins for CAR T cell therapy |
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| 500 | |a Date Revised 15.08.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. The Author(s). | ||
| 520 | |a BACKGROUND: In many situations, the therapeutic efficacy of CAR T cells is limited due to immune suppression and poor persistence. Immunostimulatory fusion protein (IFP) constructs have been advanced as a tool to convert suppressive signals into stimulation and thus promote the persistence of T cells, but no universal IFP design has been established so far. We now took advantage of a PD-1-CD28 IFP as a clinically relevant structure to define key determinants of IFP activity | ||
| 520 | |a METHODS: We compared different PD-1-CD28 IFP variants in a human leukemia model to assess the impact of distinctive design choices on CAR T cell performance in vitro and a xenograft mouse model | ||
| 520 | |a RESULTS: We observed that IFP constructs that putatively exceed the extracellular length of PD-1 induce T-cell response without CAR target recognition, rendering them unsuitable for tumour-specific therapy. IFP variants with physiological PD-1 length ameliorated CAR T cell effector function and proliferation in response to PD-L1+ tumour cells in vitro and prolonged survival in vivo. Transmembrane or extracellular CD28 domains were found to be replaceable by corresponding PD-1 domains for in vivo efficacy | ||
| 520 | |a CONCLUSION: PD-1-CD28 IFP constructs must mimic the physiological interaction of PD-1 with PD-L1 to retain selectivity and mediate CAR-conditional therapeutic activity | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Cadilha, Bruno L |e verfasserin |4 aut | |
| 700 | 1 | |a Obeck, Hannah |e verfasserin |4 aut | |
| 700 | 1 | |a Benmebarek, Mohamed-Reda |e verfasserin |4 aut | |
| 700 | 1 | |a Märkl, Florian |e verfasserin |4 aut | |
| 700 | 1 | |a Michaelides, Stefanos |e verfasserin |4 aut | |
| 700 | 1 | |a Strzalkowski, Thaddäus |e verfasserin |4 aut | |
| 700 | 1 | |a Briukhovetska, Daria |e verfasserin |4 aut | |
| 700 | 1 | |a Müller, Philipp Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Nandi, Sayantan |e verfasserin |4 aut | |
| 700 | 1 | |a Winter, Pia |e verfasserin |4 aut | |
| 700 | 1 | |a Majed, Lina |e verfasserin |4 aut | |
| 700 | 1 | |a Grünmeier, Ruth |e verfasserin |4 aut | |
| 700 | 1 | |a Seifert, Matthias |e verfasserin |4 aut | |
| 700 | 1 | |a Rausch, Svenja |e verfasserin |4 aut | |
| 700 | 1 | |a Feuchtinger, Tobias |e verfasserin |4 aut | |
| 700 | 1 | |a Endres, Stefan |e verfasserin |4 aut | |
| 700 | 1 | |a Kobold, Sebastian |e verfasserin |4 aut | |
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