PURPOSE In classical Hodgkin lymphoma, the malignant Reed-Sternberg cells express the cell surface marker CD30. Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers a potent cytotoxic agent, monomethyl auristatin E (MMAE), to CD30-positive cells. Although brentuximab vedotin elicits a high response rate (75%) in relapsed/refractory Hodgkin lymphoma, most patients who respond to brentuximab vedotin eventually develop resistance. PATIENTS AND METHODS We developed two brentuximab vedotin-resistant Hodgkin lymphoma cell line models using a pulsatile approach and observed that resistance to brentuximab vedotin is associated with an upregulation of multidrug resistance-1 (MDR1). We then conducted a phase I trial combining brentuximab vedotin and cyclosporine A (CsA) in patients with relapsed/refractory Hodgkin lymphoma. RESULTS Here, we show that competitive inhibition of MDR1 restored sensitivity to brentuximab vedotin in our brentuximab vedotin-resistant cell lines by increasing intracellular MMAE levels, and potentiated brentuximab vedotin activity in brentuximab vedotin-resistant Hodgkin lymphoma tumors in a human xenograft mouse model. In our phase I trial, the combination of brentuximab vedotin and CsA was tolerable and produced an overall and complete response rate of 75% and 42% in a population of patients who were nearly all refractory to brentuximab vedotin. CONCLUSIONS This study may provide a new therapeutic strategy to combat brentuximab vedotin resistance in Hodgkin lymphoma. This is the first study reporting an effect of multidrug resistance modulation on the therapeutic activity of an ADC in humans. The expansion phase of the trial is ongoing and enrolling patients who are refractory to brentuximab vedotin to confirm clinical activity in this population with unmet need.

中文翻译：

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在霍奇金淋巴瘤中，MDR1的抑制作用克服了对Brentuximab Vedotin的耐药性。

目的在经典霍奇金淋巴瘤中，恶性的里德-斯特恩伯格细胞表达细胞表面标志物CD30。Brentuximab vedotin是一种抗体-药物偶联物（ADC），可将有效的细胞毒剂单甲基澳瑞他汀E（MMAE）递送至CD30阳性细胞。尽管brentuximab vedotin在复发/难治性霍奇金淋巴瘤中引起较高的应答率（75％），但大多数对brentuximab vedotin应答的患者最终会产生耐药性。患者和方法我们使用脉冲方法开发了两个耐brentuximab vedotin的霍奇金淋巴瘤细胞系模型，并观察到对brentuximab vedotin的耐药性与多药耐药性1（MDR1）的上调有关。然后，我们对复发/难治性霍奇金淋巴瘤患者进行了联合brentuximab vedotin和环孢素A（CsA）的I期试验。结果在这里，我们表明在人异种移植小鼠模型中，对MDR1的竞争性抑制通过提高细胞内MMAE水平恢复了对我们对brentuximab vedotin耐药的细胞系中对brentuximab vedotin的敏感性，并增强了对brentuximab vedotin耐药的霍奇金淋巴瘤肿瘤中增强的brentuximab vedotin活性。在我们的I期试验中，在几乎全部对brentuximab vedotin无效的患者群中，brentuximab vedotin和CsA的组合是可以耐受的，并产生了75％和42％的总体和完全缓解率。结论本研究可为霍奇金淋巴瘤抵抗布伦替昔单抗维多汀耐药提供一种新的治疗策略。这是第一项报道多药耐药性调节对ADC在人体中的治疗活性的影响的研究。