Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability
Chimeric antigen receptor-T (CAR-T) cell therapies can eliminate relapsed and refractory tumors, but the durability of antitumor activity requires in vivo persistence. Differential signaling through the CAR costimulatory domain can alter the T cell metabolism, memory differentiation, and influence long-term persistence. CAR-T cells costimulated with 4-1BB or ICOS persist in xenograft models but those constructed with CD28 exhibit rapid clearance. Here, we show that a single amino acid residue in CD28 drove T cell exhaustion and hindered the persistence of CD28-based CAR-T cells and changing this asparagine to phenylalanine (CD28-YMFM) promoted durable antitumor control. In addition, CD28-YMFM CAR-T cells exhibited reduced T cell differentiation and exhaustion as well as increased skewing toward Th17 cells. Reciprocal modification of ICOS-containing CAR-T cells abolished in vivo persistence and antitumor activity. This finding suggests modifications to the costimulatory domains of CAR-T cells can enable longer persistence and thereby improve antitumor response.
| Errataetall: |
CommentIn: J Clin Invest. 2020 Jun 1;130(6):2806-2808. - PMID 32364534 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:130 |
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| Enthalten in: |
The Journal of clinical investigation - 130(2020), 6 vom: 01. Juni, Seite 3087-3097 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Guedan, Sonia [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 02.02.2021 Date Revised 14.02.2024 published: Print CommentIn: J Clin Invest. 2020 Jun 1;130(6):2806-2808. - PMID 32364534 Citation Status MEDLINE |
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| doi: |
10.1172/JCI133215 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM306632438 |
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| 245 | 1 | 0 | |a Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability |
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| 500 | |a published: Print | ||
| 500 | |a CommentIn: J Clin Invest. 2020 Jun 1;130(6):2806-2808. - PMID 32364534 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Chimeric antigen receptor-T (CAR-T) cell therapies can eliminate relapsed and refractory tumors, but the durability of antitumor activity requires in vivo persistence. Differential signaling through the CAR costimulatory domain can alter the T cell metabolism, memory differentiation, and influence long-term persistence. CAR-T cells costimulated with 4-1BB or ICOS persist in xenograft models but those constructed with CD28 exhibit rapid clearance. Here, we show that a single amino acid residue in CD28 drove T cell exhaustion and hindered the persistence of CD28-based CAR-T cells and changing this asparagine to phenylalanine (CD28-YMFM) promoted durable antitumor control. In addition, CD28-YMFM CAR-T cells exhibited reduced T cell differentiation and exhaustion as well as increased skewing toward Th17 cells. Reciprocal modification of ICOS-containing CAR-T cells abolished in vivo persistence and antitumor activity. This finding suggests modifications to the costimulatory domains of CAR-T cells can enable longer persistence and thereby improve antitumor response | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Cancer immunotherapy | |
| 650 | 4 | |a Immunology | |
| 650 | 4 | |a T cells | |
| 650 | 4 | |a Therapeutics | |
| 650 | 7 | |a CD28 Antigens |2 NLM | |
| 650 | 7 | |a ICOS protein, human |2 NLM | |
| 650 | 7 | |a Inducible T-Cell Co-Stimulator Protein |2 NLM | |
| 650 | 7 | |a Receptors, Chimeric Antigen |2 NLM | |
| 650 | 7 | |a TNFRSF9 protein, human |2 NLM | |
| 650 | 7 | |a Tumor Necrosis Factor Receptor Superfamily, Member 9 |2 NLM | |
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| 700 | 1 | |a Casado-Medrano, Victoria |e verfasserin |4 aut | |
| 700 | 1 | |a Shaw, Carolyn |e verfasserin |4 aut | |
| 700 | 1 | |a Wing, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Fang |e verfasserin |4 aut | |
| 700 | 1 | |a Young, Regina M |e verfasserin |4 aut | |
| 700 | 1 | |a June, Carl H |e verfasserin |4 aut | |
| 700 | 1 | |a Posey, Avery D |c Jr |e verfasserin |4 aut | |
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