Anti-Acute Myeloid Leukemia Activity of CD38-CAR-T Cells with PI3Kδ Downregulation.
Mol Pharm
; 20(5): 2426-2435, 2023 05 01.
Article
em En
| MEDLINE
| ID: mdl-37021820
ABSTRACT
We previously constructed a nanobody-based anti-CD38 chimeric antigen receptor T (CD38-CAR-T) cell efficiently against multiple myeloma. As CD38 is also expressed on most tumor cells of acute myeloid leukemia (AML), we wondered about its efficacy in treating AML. In this study, we demonstrated that our CD38-CAR-T cells effectively lysed CD38+ AML cell lines, including NB4, U937, HL-60, THP-1 with an ET (effector/target cells) ratio of 18, and primary AML cells from patients with a low ET ratio of 116. Moreover, recent studies showed that inhibition of PI3Kδ could enhance CAR-T-cell efficacy. We constructed PI3Kδ-downregulated CD38-CAR-T cells with a CD38-CAR lentiviral vector containing short hairpin RNA (shRNA) sequences against PI3Kδ. CD38-CAR-T cells with PI3Kδ downregulation maintained their antileukemia function against both AML cell lines and primary AML cells while reducing the release of IL-2, IFN-γ, and TNF when co-culturing with AML cell lines. Both CD38-CAR-T and PI3Kδ-downregulated CD38-CAR-T-cell therapy significantly improved the survival of AML mice, whereas the latter had an even better effect on survival. In summary, our study demonstrated that CD38-CAR-T cells had promising activity against AML, and PI3Kδ downregulation in CD38-CAR-T cells could reduce some cytokines release without impairing their antileukemia function.
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Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Leucemia Mieloide Aguda
/
Receptores de Antígenos Quiméricos
Limite:
Animals
Idioma:
En
Revista:
Mol Pharm
Assunto da revista:
BIOLOGIA MOLECULAR
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FARMACIA
/
FARMACOLOGIA
Ano de publicação:
2023
Tipo de documento:
Article