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Cited by 547CAR-T cell therapy researchT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency

Open access
Feucht, Judith, Sun, Jie, Eyquem, Justin, Ho, Yu-Jui, Zhao, Zeguo, Leibold, Josef, Dobrin, Anton, Cabriolu, Annalisa +2 more·2019·Nature Medicine
DOI 10.1038/s41591-018-0290-5PMC PMC6532069
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Abstract

Chimeric antigen receptors (CARs) are synthetic receptors that target and reprogram T cells to acquire augmented antitumor properties 1. CD19-specific CARs that comprise CD28 and CD3ζ signaling motifs 2 have induced remarkable responses in patients with refractory leukemia 3-5 and lymphoma 6 and were recently approved by the US Food and Drug Administration 7. These CARs program highly performing effector functions that mediate potent tumor elimination 4,8 despite the limited persistence they confer on T cells 3-6,8. Extending their functional persistence without compromising their potency should improve current CAR therapies. Strong T cell activation drives exhaustion 9,10, which may be accentuated by the redundancy of CD28 and CD3ζ signaling 11,12 as well as the spatiotemporal constraints imparted by the structure of second-generation CARs 2. Thus, we hypothesized that calibrating the activation potential of CD28-based CARs would differentially reprogram T cell function and differentiation. Here, we show that CARs encoding a single immunoreceptor tyrosine-based activation motif direct T cells to different fates by balancing effector and memory programs, thereby yielding CAR designs with enhanced therapeutic profiles.

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Cited by

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Authors
Feucht, J., Sun, J., Eyquem, J., Ho, Y.-J., Zhao, Z., Leibold, J., Dobrin, A., Cabriolu, A., Hamieh, M., & Sadelain, M.
Affiliations
Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Sadelain, Michel
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2018-12-17
Volume
25
Issue
1
Pages
82-88
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-018-0290-5
PMC
PMC6532069
OpenAlex
W2903960245
Cited by
547
References
7
Citations by year
2026: 66 · 2025: 82 · 2024: 72 · 2023: 69 · 2022: 68 · 2021: 87 · 2020: 72 · 2019: 29
FWCI
17.67
Type
journal article
Language
en
Update notices
correction (2019-01-28)
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Commonwealth Foundation
  • Memorial Sloan-Kettering Cancer Center
  • Broad Institute
  • National Cancer Institute (P30CA008748)
Topics
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
chimeric antigen receptor T cells, CD28 signaling, CD3 signaling, ITAM, T cell exhaustion, T cell persistence
MeSH terms
Protein Domains, Animals, Calibration, Cell Line, Immunotherapy, Male, Receptors, Antigen, T-Cell, T-Lymphocytes, Cell Lineage, Mice

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