Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking
Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking
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DOI：
10.1182/blood-2016-05-718395
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发表时间：
2017-01-05
期刊：
影响因子：
20.3
通讯作者：
Binder, Mascha
中科院分区：
文献类型：
--
作者：
Braig, Friederike;Brandt, Anna;Binder, Mascha
CD19抗原是急性淋巴细胞白血病（ALL）免疫治疗的一个有希望的靶点，但CD19（-）复发仍然是约10%至20%患者的主要挑战。在这里，我们分析了使用CD19/CD3双特异性t细胞接触器（BiTE） blinatumumab治疗后的4例CD19(-) ALL复发。其中3例为药物复发，仅在2个疗程后首次检测到CD19（-）逃逸变体。在1例患者中，CD19（-）克隆在完成blinatumumab治疗19个月后出现晚期复发。除CD19阴性外，所有4例患者的细胞表型与原发性诊断相同。这有力地支持了一个孤立的分子事件，并反对共同淋巴细胞CD19（-）祖细胞或髓系移位驱动耐药性。对1例早期复发病例的彻底分子检查证实了这一假设，发现后内质网室中CD19膜出口被破坏是blinatumab耐药的分子基础。
The CD19 antigen is a promising target for immunotherapy of acute lymphoblastic leukemia (ALL), but CD19(-) relapses remain a major challenge in about 10% to 20% of patients. Here, we analyzed 4 CD19(-) ALL relapses after treatment with the CD19/CD3 bispecific T-cell engager (BiTE) blinatumomab. Three were on-drug relapses, with the CD19(-) escape variant first detected after only 2 treatment courses. In 1 patient, the CD19(-) clone appeared as a late relapse 19 months after completion of blinatumomab treatment. All 4 cases showed a cellular phenotype identical to the primary diagnosis except for CD19 negativity. This argued strongly in favor of an isolated molecular event and against a common lymphoid CD19(-) progenitor cell or myeloid lineage shift driving resistance. A thorough molecular workup of 1 of the cases with early relapse confirmed this hypothesis by revealing a disrupted CD19 membrane export in the post-endoplasmic reticulum compartment as molecular basis for blinatumomab resistance.