PI3Kδ下调CD38-CAR-T细胞的抗急性髓性白血病活性,Molecular Pharmaceutics

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PI3Kδ下调CD38-CAR-T细胞的抗急性髓性白血病活性
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2023-04-06 , DOI: 10.1021/acs.molpharmaceut.2c00913
Na An ₁ , Yuming Pan ₁ , Linlin Yang ₁ , Qiongli Zhang ₁ , Sisi Deng ₁ , Qiaoxia Zhang ₁ , Xin Du ₁

Affiliation

我们之前构建了一种基于纳米抗体的抗 CD38 嵌合抗原受体 T (CD38-CAR-T) 细胞，可有效对抗多发性骨髓瘤。由于 CD38 也在大多数急性髓性白血病 (AML) 的肿瘤细胞上表达，我们想知道它在治疗 AML 中的疗效。在这项研究中，我们证明我们的 CD38-CAR-T 细胞可有效裂解 CD38 ⁺AML 细胞系，包括 NB4、U937、HL-60、E:T（效应细胞/靶细胞）比例为 1:8 的 THP-1，以及来自低 E:T 比例为 1:16 的患者的原代 AML 细胞. 此外，最近的研究表明，抑制 PI3Kδ 可以增强 CAR-T 细胞的功效。我们使用含有针对 PI3Kδ 的短发夹 RNA (shRNA) 序列的 CD38-CAR 慢病毒载体构建了 PI3Kδ 下调的 CD38-CAR-T 细胞。具有 PI3Kδ 下调的 CD38-CAR-T 细胞在与 AML 细胞系共培养时保持其针对 AML 细胞系和原代 AML 细胞的抗白血病功能，同时减少 IL-2、IFN-γ 和 TNF 的释放。CD38-CAR-T 和 PI3Kδ 下调 CD38-CAR-T 细胞疗法均显着改善了 AML 小鼠的存活率，而后者对存活率的影响甚至更好。总之，

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Anti-Acute Myeloid Leukemia Activity of CD38-CAR-T Cells with PI3Kδ Downregulation

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 E:T (effector/target cells) ratio of 1:8, and primary AML cells from patients with a low E:T ratio of 1:16. 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.

更新日期：2023-04-06

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