Division of Hematology, Oncology, and Transplantation, Department of Medicine, and.
Department of Radiation Oncology, University of Minnesota, Minneapolis, MN.
Blood Adv. 2019 Mar 26;3(6):897-907. doi: 10.1182/bloodadvances.2018029371.
Chronic lymphocytic leukemia (CLL) is characterized by chronic clonal expansion of mature CD19-expressing B lymphocytes and global dysfunction of immune effectors, including natural killer (NK) cells. CLL remains incurable, and novel approaches to refractory CLL are needed. Our group has previously described trispecific killer engager (TriKE) molecules that redirect NK cell function against tumor cells. TriKE reagents simultaneously bind an activating receptor on NK cells, CD16, and a tumor antigen while also providing an NK cell expansion signal via an interleukin-15 moiety. Here we developed the novel CD19-targeting 161519 TriKE. We demonstrate that 161519 TriKE induced killing of a CD19-expressing Burkitt's lymphoma cell line and examined the impact on primary CLL targets using healthy donor and patient NK cells. 161519 TriKE induced potent healthy donor NK cell activation, proliferation, and directed killing. Furthermore, 161519 TriKE rescued the inflammatory function of NK cells obtained from CLL patient peripheral blood samples. Finally, we show that 161519 TriKE induced better directed killing of CLL in vitro when compared with rituximab. In conclusion, 161519 TriKE drives a potent activating and proliferative signal on NK cells, resulting in enhanced NK cell expansion and CLL target killing. Our findings indicate the potential immunotherapeutic value of 161519 TriKE in CLL.
慢性淋巴细胞白血病（CLL）的特征是成熟 CD19 表达 B 淋巴细胞的慢性克隆性扩张和免疫效应器的整体功能障碍，包括自然杀伤（NK）细胞。CLL 仍然无法治愈，需要新的方法来治疗难治性 CLL。我们的小组之前描述了三特异性杀伤剂（TriKE）分子，这些分子将 NK 细胞的功能重新定向到肿瘤细胞上。TriKE 试剂同时结合 NK 细胞上的激活受体 CD16 和肿瘤抗原，同时通过白细胞介素-15 部分提供 NK 细胞扩增信号。在这里，我们开发了新型的 CD19 靶向 161519 TriKE。我们证明 161519 TriKE 诱导表达 CD19 的 Burkitt 淋巴瘤细胞系的杀伤，并使用健康供体和患者 NK 细胞检查对原发性 CLL 靶标的影响。161519 TriKE 诱导健康供体 NK 细胞的有效激活、增殖和定向杀伤。此外，161519 TriKE 挽救了从 CLL 患者外周血样本中获得的 NK 细胞的炎症功能。最后，我们表明与利妥昔单抗相比，161519 TriKE 在体外诱导更好的 CLL 定向杀伤。总之，161519 TriKE 在 NK 细胞上驱动强大的激活和增殖信号，导致 NK 细胞的扩增和 CLL 靶标杀伤增强。我们的研究结果表明 161519 TriKE 在 CLL 中具有潜在的免疫治疗价值。
