Ella Troy , Joseph Caporale , Yasemin Sezgin , Marcelo S. F. Pereira , Gregory Behbehani , Justin Lyberger , Dean A. Lee ∗ , Meisam Naeimi Kararoudi ∗
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引用次数: 0
Abstract
CD38 is a metabolically active enzyme broadly expressed on the surface of normal and malignant hematologic cells. It has been targeted clinically with anti-CD38 monoclonal antibodies (mAbs), for which efficacy may be limited by natural killer (NK)–cell fratricide. Isatuximab is an anti-CD38 mAb that uniquely inhibits CD38 metabolic activity. Here, we used CRISPR/adeno-associated virus (AAV) to generate fratricide–resistant and metabolically–enhanced CD38KO/CD38-chimeric antigen receptor (CAR) NK cells using 2 isatuximab-based CD38 single-chain variable fragments (scFvs; reversing heavy and light chain orientation) on the same CD8α/4-1BB/CD3ζ base, and we demonstrate their activity against a range of CD38+ hematologic malignancies (acute myeloid leukemia, multiple myeloma, Burkitt lymphoma, and T-cell leukemia/lymphoma). The cytotoxicity of the CAR NK cells was enhanced by upregulating CD38 expression on the malignant targets with all-trans retinoic acid (ATRA). By generating CD38KO/CD38-CAR T cells using the same engineering approach, we show that the CAR NK cells had higher cytotoxicity than CAR T cells against all hematologic tumor targets. Additionally, AAVS1KO/CD38-CAR NK cells were capable of targeting CD38 without experiencing fratricide and have a similar enhanced metabolic activity via the inhibitory activity of the cis-acting isatuximab-based scFv. Finally, we report fratricide-resistant CD38-CAR NK cells with enhanced metabolism and cytotoxicity toward CD38+ hematologic malignancies, further increased by combination treatment with ATRA.
CD38-CAR 人 NK 细胞与 ATRA 结合使用可增强对表达 CD38 的血液恶性肿瘤的细胞毒性
摘要CD38是一种代谢活性酶，广泛表达于正常和恶性血液细胞表面。临床上，抗 CD38 单克隆抗体（mAbs）一直以其为靶点，但其疗效可能会受到自然杀伤（NK）细胞自相残杀的限制。伊沙妥昔单抗是一种抗 CD38 mAb，它能独特地抑制 CD38 的代谢活性。在这里，我们使用 CRISPR/腺相关病毒（AAV）生成了抗自相残杀和代谢增强的 CD38KO/CD38-嵌合抗原受体（CAR）NK 细胞，其中使用了 2 种基于伊沙妥昔单抗的 CD38 单链可变片段（scFvs；我们证明了它们对一系列 CD38+ 血液恶性肿瘤（急性髓性白血病、多发性骨髓瘤、伯基特淋巴瘤和 T 细胞白血病/淋巴瘤）的活性。）通过全反式维甲酸（ATRA）上调恶性肿瘤靶点的 CD38 表达，增强了 CAR NK 细胞的细胞毒性。通过使用相同的工程方法生成 CD38KO/CD38-CAR T 细胞，我们发现 CAR NK 细胞比 CAR T 细胞对所有血液肿瘤靶点都具有更高的细胞毒性。此外，AAVS1KO/CD38-CAR NK 细胞能够靶向 CD38，而不会发生自相残杀，并且通过顺式作用的伊沙妥昔单抗 scFv 的抑制活性增强了类似的代谢活性。最后，我们报告了抗自相残杀的 CD38-CAR NK 细胞，它们的代谢能力和对 CD38+ 血液恶性肿瘤的细胞毒性都得到了增强，与 ATRA 的联合治疗进一步提高了这种能力。
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