Enhanced antitumor efficacy, proliferative capacity, and alleviation of T cell exhaustion by fifth-generation chimeric antigen receptor T cells targeting B cell maturation antigen in multiple myeloma - 11/11/23
Abstract |
Chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) has been approved for treating multiple myeloma (MM). Some clinical studies reported suboptimal outcomes, including reduced cytotoxicity of CAR-T cells and tumor evasion through increased expression of programmed death-ligand 1 (PD-L1). To enhance CAR-T cell efficiency and overcome PD-L1-mediated T cell suppression, we developed anti-BCMA-CAR5-T cells equipped with three costimulatory domains and the ability to secrete anti-PD-L1 single-chain variable fragment (scFv) blockade molecules. Anti-BCMA-CAR4-T cells contained a fully human anti-BCMA scFv and three intracellular domains (CD28, 4–1BB, and CD27) joined with CD3ζ. Anti-BCMA-CAR5-T cells were generated by fusing anti-BCMA-CAR4 with anti-PD-L1 scFv. Both anti-BCMA-CAR4-T and anti-BCMA-CAR5-T cells demonstrated comparable antitumor activity against parental MM cells. However, at an effector-to-target ratio of 1:2, only anti-BCMA-CAR5-T cells maintained cytolytic activity against PD-L1 high MM cells, unlike anti-BCMA-CAR4 T cells. Anti-BCMA-CAR5-T cells were specifically activated by BCMA-expressing target cells, resulting in increased CAR-T cell proliferation, release of cytolytic mediators, and pro-inflammatory cytokines. Anti-BCMA-CAR5-T cells demonstrated specific cytotoxicity against BCMA-expressing target cells, leading to decreased target cell numbers, increased CAR-T cell numbers, and preserved CAR expression during antigenic re-stimulation. Interestingly, only anti-BCMA-CAR5-T cells showed reduced PD-1 receptor levels, which correlated with decreased PD-L1 expression on target cells. We successfully generated anti-BCMA-CAR5-T cells capable of secreting anti-PD-L1 scFv. These cells exhibited superior antitumor efficiency, proliferative capacity, and alleviated T-cell exhaustion against MM cells. Further investigation into the antitumor efficacy of anti-BCMA-CAR5-T cells is warranted in ex vivo and clinical research settings.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | Anti-BCMA-CAR5-T cells exhibit heightened antitumor efficacy, attributable to their secretion of anti-PD-L1 scFv. |
• | The presence of anti-PD-L1 scFv enhances the proliferation of anti-BCMA-CAR5-T cells, achieved through the PD-L1 blockade. |
• | Anti-BCMA-CAR5-T cells bolstered with anti-PD-L1 scFv reduce T cell exhaustion and restore their antitumor function. |
Abbreviations : BCMA, CD3, CD4, CD8, CD19, CD25, CD27, CD28, CD69, PBMC, TNFα, IFNγ, IL-2, IL-4, IL-6, IL-7, IL-10, IL-15, MHC, MM, RR, CAR, FDA, scFv, HA tag, SDS-PAGE, PHA, PD-l, PD-L1, TIM-3, LAG-3
Keywords : Multiple myeloma, BCMA, Chimeric antigen receptor, CAR, Anti-PD-L1 scFv, Immune checkpoint blockade
Plan
Vol 168
Article 115691- décembre 2023 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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