التفاصيل البيبلوغرافية
| العنوان: |
A novel method to generate T-cell receptor–deficient chimeric antigen receptor T cells |
| المؤلفون: |
Takahiro Kamiya, Desmond Wong, Yi Tian Png, Dario Campana |
| المصدر: |
Blood Advances, Vol 2, Iss 5, Pp 517-528 (2018) |
| بيانات النشر: |
Elsevier, 2018. |
| سنة النشر: |
2018 |
| المجموعة: |
LCC:Specialties of internal medicine |
| مصطلحات موضوعية: |
Specialties of internal medicine, RC581-951 |
| الوصف: |
Abstract: Practical methods are needed to increase the applicability and efficacy of chimeric antigen receptor (CAR) T-cell therapies. Using donor-derived CAR-T cells is attractive, but expression of endogenous T-cell receptors (TCRs) carries the risk for graft-versus-host-disease (GVHD). To remove surface TCRαβ, we combined an antibody-derived single-chain variable fragment specific for CD3ε with 21 different amino acid sequences predicted to retain it intracellularly. After transduction in T cells, several of these protein expression blockers (PEBLs) colocalized intracellularly with CD3ε, blocking surface CD3 and TCRαβ expression. In 25 experiments, median TCRαβ expression in T lymphocytes was reduced from 95.7% to 25.0%; CD3/TCRαβ cell depletion yielded virtually pure TCRαβ-negative T cells. Anti-CD3ε PEBLs abrogated TCRαβ-mediated signaling, without affecting immunophenotype or proliferation. In anti-CD3ε PEBL-T cells, expression of an anti-CD19-41BB-CD3ζ CAR induced cytokine secretion, long-term proliferation, and CD19+ leukemia cell killing, at rates meeting or exceeding those of CAR-T cells with normal CD3/TCRαβ expression. In immunodeficient mice, anti-CD3ε PEBL-T cells had markedly reduced GVHD potential; when transduced with anti-CD19 CAR, these T cells killed engrafted leukemic cells. PEBL blockade of surface CD3/TCRαβ expression is an effective tool to prepare allogeneic CAR-T cells. Combined PEBL and CAR expression can be achieved in a single-step procedure, is easily adaptable to current cell manufacturing protocols, and can be used to target other T-cell molecules to further enhance CAR-T-cell therapies. |
| نوع الوثيقة: |
article |
| وصف الملف: |
electronic resource |
| اللغة: |
English |
| تدمد: |
2473-9529 |
| Relation: |
http://www.sciencedirect.com/science/article/pii/S2473952920310752; https://doaj.org/toc/2473-9529 |
| DOI: |
10.1182/bloodadvances.2017012823 |
| URL الوصول: |
https://doaj.org/article/c2087e3a41dd420c97c6b90004e38cd0 |
| رقم الانضمام: |
edsdoj.2087e3a41dd420c97c6b90004e38cd0 |
| قاعدة البيانات: |
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