Exploiting Natural Killer Cell Engagers to Control Pediatric B-cell Precursor Acute Lymphoblastic Leukemia.
Exploiting Natural Killer Cell Engagers to Control Pediatric B-cell Precursor Acute Lymphoblastic Leukemia.
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DOI：
10.1158/2326-6066.cir-21-0843
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发表时间：
2022-03-01
影响因子：
10.1
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中科院分区：
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NK 细胞接合剂 (NKCE) 可以增强 NK 细胞介导的对儿童 BCP-ALL 的杀伤，特别是当使用靶向 CD19 的 NKCE 将 NKp46 与 CD16A 结合在一起时。这些数据支持临床使用 NKCE 治疗 BCP-ALL 患者。自然杀伤 (NK) 细胞在抗肿瘤免疫治疗中代表着一种有前景的细胞类型，具有疗效和安全性，特别是在血液恶性肿瘤的治疗中。 NK 细胞已被证明在单倍体相合造血干细胞移植 (haplo-HSCT) 中发挥抗白血病活性。已开发出的产品仅在与肿瘤细胞交联时增强 NK 细胞的激活，避免任何脱靶效应。在这里，我们测试了不同 NK 细胞接合剂 (NKCE) 的体外效果，这些接合剂触发 NKp46 或 NKp30 与 CD16A，并靶向 CD19 或 CD20 以诱导杀伤儿童 B 细胞前体急性淋巴细胞白血病 (BCP-ALL)。靶细胞是 NALM-16 和 MHH-CALL-4 细胞系和四种原发性白血病，而效应细胞是来自健康供体和 αβT/B 耗尽单倍体 HSCT 后患有白血病的儿科患者的静息 NK 细胞。使用所有 NKCE 均能有效杀死 NK 细胞耐药性 MHH-CALL-4。脱颗粒和 IFNγ 的产生也明显增强了 NK 针对 MHH-CALL-4 的活性。由于原发性 BCP-ALL 缺乏 CD20 且 CD19 高表达，因此我们重点关注靶向 CD19 的 NKCE。基于 NKp46 和 NKp30 的 NKCE 在诱导 NK 细胞活性方面表现出相似的效力，即使在受到原代 BCP-ALL 母细胞攻击时也是如此。使用来自移植患者的 NK 细胞也显示了它们的功效。 NKCE 诱导的针对 BCP-ALL 的激活可以超越 HLA 特异性抑制相互作用，尽管同种反应性 NK 细胞亚群观察到最强的反应。这些数据支持 NKp46/CD16A/CD19-NKCE 在移植前或移植后环境中治疗难治性/复发性白血病。
NK-cell engagers (NKCE) can enhance NK cell–mediated killing of pediatric BCP-ALL, particularly when using a CD19-targeting NKCE that engages NKp46 together with CD16A. The data support the clinical use of NKCEs to treat patients with BCP-ALL. Natural killer (NK) cells represent a promising cell type in antitumor immunotherapy for efficacy and safety, particularly in the treatment of hematologic malignancies. NK cells have been shown to exert antileukemia activity in the context of haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Products have been developed to boost the activation of NK cells only when cross-linked by tumor cells, avoiding any off-target effect. Here, we tested the in vitro effect of different NK-cell engagers (NKCE), which trigger either NKp46 or NKp30 together with CD16A, and target either CD19 or CD20 to induce killing of pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Target cells were NALM-16 and MHH-CALL-4 cell lines and four primary leukemias, while effector cells were resting NK cells derived from healthy donors and pediatric patients with leukemia after αβT/B-depleted haplo-HSCT. The NK cell–resistant MHH-CALL-4 was efficiently killed using all NKCEs. Boosting of NK activity against MHH-CALL-4 was also evident by degranulation and IFNγ production. Because of the lack of CD20 and high expression of CD19 on primary BCP-ALL, we focused on NKCEs targeting CD19. NKp46- and NKp30-based NKCEs displayed similar potency at inducing NK-cell activity, even when challenged with primary BCP-ALL blasts. Their efficacy was shown also using NK cells derived from transplanted patients. NKCE-induced activation against BCP-ALL can override HLA-specific inhibitory interactions, although the strongest response was observed by the alloreactive NK-cell subset. These data support the therapeutic use of NKp46/CD16A/CD19-NKCE to fight refractory/relapsed leukemia in pretransplantation or posttransplantation settings.