Immediate hypersensitivity reactions (iHSRs) to taxanes are observed in 6% and 4% of gynecologic and breast cancer patients, respectively. Drug desensitization is the only option, as no comparable alternative therapy is available. Surfactants in the taxane formulation have been implicated in the immunopathogenesis of iHSRs, although sporadic skin test (ST) positivity and iHSRs to nab-paclitaxel have suggested the involvement of the taxane moiety and/or IgE-mediated pathomechanisms. In vitro diagnostic tests might offer insights into mechanisms underlying iHSRs to taxanes. The aim of the present study was to address this unmet need by developing a novel basophil activation test (BAT). The study included patients (n= 31) undergoing paclitaxel/carboplatin therapy. Seventeen patients presented with iHSRs to paclitaxel (iHSR-Taxpos), and eleven were tolerant (iHSR-Taxneg). Fourteen patients presented with iHSRs to carboplatin (iHSR-Plpos), and fourteen were tolerant (iHSR-Plneg). The BAT median stimulation index (SI) values were 1.563 (range, 0.02–4.11;n= 11) and −0.28 (range −4.88–0.07,n= 11) in iHSR-Taxposand iHSR-Taxneg, respectively. The BAT median SI values were 4.45 (range, 0.1–26.7;n= 14) and 0 (range, −0.51–1.65;n= 12) in iHSR-Plposand iHSR-Plneg, respectively. SI levels were not associated with iHSR severity grading. Comparing BAT results in iHSR-Taxposand iHSR-Taxnegshowed the area under the receiver operator characteristic (ROC) curve to be 0.9752 (p= 0.0002). The cutoff calculated by the maximized likelihood ratio identified 90.91% of iHSR-Taxpospatients and 90.91% of iHSR-Taxnegpatients. Comparing BAT results for iHSR-Plposand iHSR-Plnegshowed the area under the ROC curve to be 0.9286 (p= 0.0002). The cutoff calculated by the maximized likelihood ratio identified 78.57% of iHSR-Plpospatients and 91.67% of iHSR-Plnegpatients. Most iHSR-Taxpospatients for which ST was available (10/11) scored ST-negative and BAT-positive, whereas most iHSR-Plpospatients for which ST was available (14/14) scored both BAT- and ST-positive. This suggested the intervention of non-IgE-mediated mechanisms in iHSR-Taxpospatients. Consistent with this view, an in silico molecular docking analysis predicted the high affinity of paclitaxel to the degranulation-competent MRGPRX2 receptor. This hypothesis warrants further in vitro investigations. In conclusion, the present study provides preliminary proof-of-concept evidence that this novel BAT has potential utility in understanding mechanisms underlying iHSRs to taxanes.
紫杉类药物速发型超敏反应在妇科和乳腺癌患者中的发生率分别为6%和4%。由于缺乏可替代治疗方案，药物脱敏成为唯一选择。尽管紫杉醇制剂中的表面活性剂被认为参与速发型超敏反应的免疫病理机制，但白蛋白结合型紫杉醇偶发的皮肤试验阳性及超敏反应提示紫杉烷结构单元和/或IgE介导的病理机制可能参与其中。体外诊断检测或可为阐明紫杉类药物超敏反应机制提供新见解。本研究旨在通过开发新型嗜碱性粒细胞活化试验来填补这一空白。研究纳入31例接受紫杉醇/卡铂治疗的患者，其中17例出现紫杉醇超敏反应，11例耐受；14例出现卡铂超敏反应，14例耐受。嗜碱性粒细胞活化试验结果显示：紫杉醇超敏反应组刺激指数中位值为1.563（范围0.02-4.11），耐受组为-0.28（范围-4.88-0.07）；卡铂超敏反应组刺激指数中位值为4.45（范围0.1-26.7），耐受组为0（范围-0.51-1.65）。刺激指数水平与超敏反应严重程度分级无相关性。受试者工作特征曲线分析显示：紫杉醇组曲线下面积为0.9752（p=0.0002），通过最大似然比计算的界值可识别90.91%的超敏反应患者和90.91%的耐受患者；卡铂组曲线下面积为0.9286（p=0.0002），相应界值可识别78.57%的超敏反应患者和91.67%的耐受患者。在可获得皮肤试验结果的紫杉醇超敏反应患者中（11/17），多数（10/11）表现为皮肤试验阴性而嗜碱性粒细胞活化试验阳性；而卡铂超敏反应患者（14/14）则多表现为两种检测同时阳性，提示紫杉醇超敏反应可能涉及非IgE介导的机制。分子对接模拟分析预测紫杉醇与具备脱颗粒功能的MRGPRX2受体具有高亲和力，该假说有待进一步体外实验验证。本研究初步证明新型嗜碱性粒细胞活化试验在解析紫杉类药物超敏反应机制方面具有潜在应用价值。
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