B cell acute lymphoblastic leukemia (B-ALL) is characterized by an accumulation of malignant precursor cells. Treatment consists of multiagent chemotherapy followed by allogeneic stem cell transplantation in high-risk patients. In addition, patients bearing the BCR-ABL1 fusion gene receive concomitant tyrosine kinase inhibitor (TKI) therapy. On the other hand, monoclonal antibody therapy is increasingly used in both clinical trials and real-world settings. The introduction of rituximab has improved the outcomes in CD20 positive cases. Other monoclonal antibodies, such as tafasitamab (anti-CD19), obinutuzumab (anti-CD20) and epratuzumab (anti-CD22) have been tested in trials (NCT05366218, NCT04920968, NCT00098839). The efficacy of monoclonal antibodies is based, at least in part, on their ability to induce antibody-dependent cellular cytotoxicity (ADCC). Combination treatments, e.g., chemotherapy and TKI, should therefore be screened for potential interference with ADCC. Here, we report on in vitro data using BCR-ABL1 positive and negative B-ALL cell lines treated with rituximab and TKI. NK cell activation, proliferation, degranulation, cytokine release and tumor cell lysis were analyzed. In contrast to ATP site inhibitors such as dasatinib and ponatinib, the novel first-in-class selective allosteric ABL myristoyl pocket (STAMP) inhibitor asciminib did not significantly impact ADCC in our settings. Our results suggest that asciminib should be considered in clinical trials.
B细胞急性淋巴细胞白血病（B-ALL）的特征在于恶性前体细胞的积累。治疗包括多药化疗，高危患者随后接受异基因干细胞移植。此外，携带BCR-ABL1融合基因的患者需同时接受酪氨酸激酶抑制剂（TKI）治疗。另一方面，单克隆抗体疗法在临床试验和实际临床应用中日益广泛。利妥昔单抗的引入改善了CD20阳性患者的预后。其他单克隆抗体，如他法西他单抗（抗CD19）、奥滨尤妥珠单抗（抗CD20）和依帕珠单抗（抗CD22）已在临床试验中进行测试（NCT05366218、NCT04920968、NCT00098839）。单克隆抗体的疗效至少部分基于其诱导抗体依赖性细胞介导的细胞毒作用（ADCC）的能力。因此，应筛选联合治疗方案（如化疗与TKI）对ADCC的潜在干扰。本文报告了使用利妥昔单抗和TKI处理BCR-ABL1阳性和阴性B-ALL细胞系的体外实验数据，分析了NK细胞的活化、增殖、脱颗粒、细胞因子释放及肿瘤细胞裂解情况。与达沙替尼和普纳替尼等ATP位点抑制剂不同，新型首创选择性变构ABL肉豆蔻酰口袋（STAMP）抑制剂阿西米尼在我们的实验条件下未显著影响ADCC。研究结果表明，阿西米尼值得在临床试验中进一步探索。
Asciminib Maintains Antibody-Dependent Cellular Cytotoxicity against Leukemic Blasts
肿瘤(癌症)患者之家