Combination Therapy for Treating Advanced Drug-Resistant Acute Lymphoblastic Leukemia.
Combination Therapy for Treating Advanced Drug-Resistant Acute Lymphoblastic Leukemia.
复制标题
治疗晚期耐药急性淋巴细胞白血病的联合疗法。
DOI：
10.1158/2326-6066.cir-19-0058
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发表时间：
2019
影响因子：
10.1
通讯作者：
Parameswaran,Reshmi
中科院分区：
文献类型：
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作者：
Vicioso,Yorleny;Gram,Hermann;Beck,Rose;Asthana,Abhishek;Zhang,Keman;Wong,DerekP;Letterio,John;Parameswaran,Reshmi
耐药急性淋巴细胞白血病（ALL）患者对标准化疗无反应，迫切需要开发新的治疗策略。我们的研究利用了B细胞活化因子受体（BAFF-R）作为治疗靶点的耐药B-ALL细胞表面上的存在。我们使用针对自然杀伤（NK）细胞介导的抗体依赖性细胞毒性（ADCC）优化的抗BAFF-R（VAY 736）来杀死耐药ALL细胞。VAY 736抗体和NK细胞治疗显著降低了ALL疾病负担，并提供了体内存活益处。然而，如果疾病进展，NK细胞的ADCC功效被微环境转化生长因子β（TGFβ）抑制。使用TGFβ受体1（R1）抑制剂（EW-7197）抑制NK细胞中的TGFβ信号传导可显著增强VAY 736诱导的NK细胞介导的ALL杀伤。我们的研究结果强调了使用VAY 736抗体与EW-7197的组合来治疗晚期耐药B-ALL患者的潜力。
Drug-resistant acute lymphoblastic leukemia (ALL) patients do not respond to standard chemotherapy, and an urgent need exists to develop new treatment strategies. Our study exploited the presence of B-cell activating factor receptor (BAFF-R) on the surface of drug-resistant B-ALL cells as a therapeutic target. We used anti–BAFF-R (VAY736), optimized for natural killer (NK) cell–mediated antibody-dependent cellular cytotoxicity (ADCC), to kill drug-resistant ALL cells. VAY736 antibody and NK cell treatments significantly decreased ALL disease burden and provided survival benefitin vivo. However, if the disease was advanced, the ADCC efficacy of NK cells was inhibited by microenvironmental transforming growth factor-beta (TGFβ). Inhibiting TGFβ signaling in NK cells using the TGFβ receptor 1 (R1) inhibitor (EW-7197) significantly enhanced VAY736-induced NK cell–mediated ALL killing. Our results highlight the potential of using a combination of VAY736 antibody with EW-7197 to treat advance-stage, drug-resistant B-ALL patients.