Kverneland Anders H, Enevold Christian, Donia Marco, Bastholt Lars, Svane Inge Marie, Nielsen Claus H
Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Center for Cancer Immune Therapy, Department of Oncology and Hematology, Copenhagen University Hospital, Herlev, Denmark.
Oncoimmunology. 2018 Feb 1;7(5):e1424674. doi: 10.1080/2162402X.2018.1424674. eCollection 2018.
Checkpoint inhibitors, including the CTLA-4 blocking antibody ipilimumab, have become the new standard therapy for many metastatic cancers. Development of anti-drug antibodies (ADAs) after treatment with other biopharmaceuticals has been thoroughly described, but the induction of ADAs after treatment with checkpoint inhibitors has been inadequately investigated. In this retrospective study, we relate ipilimumab serum levels and anti-ipilimumab antibody levels to clinical outcomes in patients with metastatic melanoma (MM). Serum samples from 31 patients with MM were analyzed for serum levels of ipilimumab and ADAs to ipilimumab at baseline, and before the 2 and 4 infusion using an in-house bead-based assay. The results were correlated with progression-free survival (PFS) and overall survival (OS). Low serum levels of ipilimumab before the 2 infusion correlated significantly with a shorter OS (p = 0.01) and PFS (p = 0.02). Eight patients (26%) were ADA-positive at either timepoint. ADA positivity correlated significantly with a shorter OS (p = 0.03) with a hazard ratio (HR) of 3.0 (95% CI: 1.2-7.8). Four of 8 ADA-positive patients (50%) discontinued therapy before the 4 infusion due to disease progression, compared to three of 23 (13%) ADA-negative patients. We confirm that low serum levels of ipilimumab are associated with a shortened OS, and we show for the first time that ADAs to ipilimumab are associated with shorter OS in patients with MM.
包括CTLA-4阻断抗体伊匹单抗在内的检查点抑制剂已成为许多转移性癌症的新标准疗法。使用其他生物制药治疗后抗药抗体（ADA）的产生已得到充分描述，但检查点抑制剂治疗后ADA的诱导情况尚未得到充分研究。在这项回顾性研究中，我们将伊匹单抗血清水平和抗伊匹单抗抗体水平与转移性黑色素瘤（MM）患者的临床结局相关联。使用内部基于磁珠的检测方法，分析了31例MM患者的血清样本，以检测基线时、第2次和第4次输注前伊匹单抗的血清水平以及抗伊匹单抗ADA水平。结果与无进展生存期（PFS）和总生存期（OS）相关。第2次输注前伊匹单抗血清水平低与较短的OS（p = 0.01）和PFS（p = 0.02）显著相关。8名患者（26%）在任一时刻点ADA呈阳性。ADA阳性与较短的OS显著相关（p = 0.03），风险比（HR）为3.0（95%CI：1.2 - 7.8）。8名ADA阳性患者中有4名（50%）在第4次输注前因疾病进展而停止治疗，相比之下，23名ADA阴性患者中有3名（13%）。我们证实伊匹单抗血清水平低与OS缩短相关，并且我们首次表明MM患者中抗伊匹单抗ADA与较短的OS相关。
