肿瘤细胞治疗研究
英文原题：Asciminib stands out as the superior tyrosine kinase inhibitor to combine with anti-CD20 monoclonal antibodies for the treatment of CD20(+) Philadelphia-positive B-cell precursor acute lymphoblastic leukemia in preclinical models.
Asciminib stands out as the superior tyrosine kinase inhibitor to combine with anti-CD20 monoclonal antibodies for the treatment of CD20(+) Philadelphia-positive B-cell precursor acute lymphoblastic leukemia in preclinical models.
我们的结果表明，与其他 TKI 相比，asciminib 可能更适合与抗 CD20 单克隆抗体联合治疗。
费城染色体阳性 B 细胞前体急性淋巴细胞白血病（Ph+ BCP-ALL）是一种高危 ALL 亚型，其特征是存在 BCR::ABL1 融合基因。酪氨酸激酶抑制剂（TKI）联合化疗已确立为一线治疗。对于 CD20+ 原始细胞比例达到 20% 的成人 BCP-ALL 患者，还会给予抗 CD20 单克隆抗体利妥昔单抗。本研究观察到确诊 Ph+ BCP-ALL 患者中 CD20 表达较为普遍，提示利妥昔单抗联合 TKI 可能具有广泛临床应用价值。因此，我们通过评估细胞表面 CD20 水平和开展体外功能实验，考察 TKI 对抗 CD20 单克隆抗体抗肿瘤效能的影响。所有受试 TKI 均一致下调白血病细胞 CD20 表达，降低利妥昔单抗介导的补体依赖性细胞毒作用。有趣的是，这些 TKI 对自然杀伤（NK）细胞介导的抗体依赖性细胞毒作用和巨噬细胞吞噬功能影响各异。阿西米尼未抑制效应细胞功能，而达沙替尼显著抑制抗 CD20 单克隆抗体介导的 NK 细胞毒作用及巨噬细胞对 BCP-ALL 细胞的吞噬。达沙替尼和普纳替尼还降低了体外 NK 细胞脱颗粒。重要的是，离体脱颗粒实验显示，口服达沙替尼会损害患者血液中的 NK 细胞活性，而阿西米尼不会。研究结果提示，与其他 TKI 相比，阿西米尼可能更适合与抗 CD20 单克隆抗体联合治疗。
Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph+ BCP-ALL) is a high-risk subtype of acute lymphoblastic leukemia characterized by the presence of the BCR::ABL1 fusion gene. Tyrosine kinase inhibitors (TKI) combined with chemotherapy are established as the first-line treatment. Additionally, rituximab, an anti-CD20 monoclonal antibody is administered to adult BCP-ALL patients with 20% CD20+ blasts. In this study, we observed a marked prevalence of CD20 expression in patients diagnosed with Ph+ BCP-ALL, indicating a potential widespread clinical application of rituximab in combination with TKI. Consequently, we examined the influence of TKI on the antitumor effectiveness of anti-CD20 monoclonal antibodies by evaluating levels of CD20 on the cell surface and conducting in vitro functional assays. All tested TKI were found to uniformly downregulate CD20 on leukemic cells, diminishing the efficacy of rituximab-mediated complement- dependent cytotoxicity. Interestingly, these TKI displayed varied effects on natural killer (NK) cell-mediated antibody- dependent cytotoxicity and macrophage phagocytic function. While asciminib demonstrated no inhibition of effector cell functions, dasatinib notably suppressed the anti-CD20-monoclonal antibody-mediated NK cell cytotoxicity and macrophage phagocytosis of BCP-ALL cells. Dasatinib and ponatinib also decreased NK cell degranulation in vitro. Importantly, oral administration of dasatinib, but not asciminib, compromised NK cell activity in patients' blood, as determined by an ex vivo degranulation assay. Our results indicate that asciminib might be preferred over other TKI for combination therapy with anti-CD20 monoclonal antibodies.
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