4-1BB Signaling Boosts the Anti-Tumor Activity of CD28-Incorporated 2nd Generation Chimeric Antigen Receptor-Modified T Cells.
Front Immunol
; 11: 539654, 2020.
Article
em En
| MEDLINE
| ID: mdl-33281809
ABSTRACT
While chimeric antigen receptor-modified T (CAR-T) cells have shown great success for the treatment of B cell leukemia, their efficacy appears to be compromised in B cell derived lymphoma and solid tumors. Optimization of the CAR design to improve persistence and cytotoxicity is a focus of the current CAR-T study. Herein, we established a novel CAR structure by adding a full length 4-1BB co-stimulatory receptor to a 28Z-based second generation CAR that targets CD20. Our data indicated that this new 2028Z-4-1BB CAR-T cell showed improved proliferation and cytotoxic ability. To further understand the mechanism of action, we found that constitutive 4-1BB sensing significantly reduced the apoptosis of CAR-T cells, enhanced proliferation, and increased NF-κB pathway activation. Consistent with the enhanced proliferation and cytotoxicity in vitro, this new structure of CAR-T cells exhibited robust persistence and anti-tumor activity in a mouse xenograft lymphoma model. This work provides evidence for a new strategy to optimize the function of CAR-T against lymphoma.
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Base de dados:
MEDLINE
Assunto principal:
Linfócitos T
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Imunoterapia Adotiva
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Antígenos CD28
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Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral
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Receptores de Antígenos Quiméricos
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Linfoma
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article