Autoantibodies May Predict Immune-Related Toxicity: Results from a Phase I Study of Intralesional Bacillus Calmette-Guérin followed by Ipilimumab in Patients with Advanced Metastatic Melanoma.
Autoantibodies May Predict Immune-Related Toxicity: Results from a Phase I Study of Intralesional Bacillus Calmette-Guérin followed by Ipilimumab in Patients with Advanced Metastatic Melanoma.
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DOI：
10.3389/fimmu.2018.00411
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发表时间：
2018
影响因子：
7.3
通讯作者：
Cebon J
中科院分区：
文献类型：
--
作者：
Da Gama Duarte J;Parakh S;Andrews MC;Woods K;Pasam A;Tutuka C;Ostrouska S;Blackburn JM;Behren A;Cebon J
免疫检查点抑制剂（ICI）彻底改变了晚期黑色素瘤的治疗。第一个证明临床益处的ICI，ipilimumab，靶向细胞毒性T淋巴细胞相关抗原-4（CTLA-4）;然而，长期总生存率仅为22%。40多年前，发现病灶内（IL）卡介苗（BCG），一种牛分枝杆菌减毒活菌株，通过刺激局部和自限性感染后的细胞介导的免疫来诱导肿瘤消退。我们评估了这两种免疫刺激剂与黑色素瘤的组合，目的是开发更有效的免疫疗法并评估毒性。在该I期研究中，患有组织学证实的III/IV期转移性黑色素瘤的患者接受IL BCG注射，随后接受多达四个周期的静脉内伊匹单抗（抗CTLA-4）（编号NCT 01838200）。该试验在前五名患者治疗后停止，因为接受递增剂量BCG的两名患者发生了伊匹单抗单药治疗典型的高级别免疫相关不良事件（irAE）。在这两名患者中，这些irAE的特征是针对自身抗原和癌抗原的自身抗体库显著增加。有趣的是，在出现症状性毒性之前的时间点检测到诱导的自身抗体。患者之间的抗原特异性没有重叠，也没有临床应答的证据。通过使用新型免疫抑制剂组合来提高缓解率的努力可能与irAE的发生率较高相关，因此确定毒性生物标志物的必要性仍然很强。虽然本试验中的患者数量较少，无法获得任何预测性生物标志物的结论性证据，但观察到的变化需要在治疗过程中有发生irAE风险的较大患者队列中进一步检查自身抗体库。总之，IL BCG的剂量递增随后伊匹单抗治疗在晚期黑素瘤患者中耐受性不佳，并且没有显示出临床益处的证据。测量自身抗体应答可能为识别癌症免疫治疗期间发生严重irAE风险的患者提供早期手段。
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced melanoma. The first ICI to demonstrate clinical benefit, ipilimumab, targets cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4); however, the long-term overall survival is just 22%. More than 40 years ago intralesional (IL) bacillus Calmette–Guérin (BCG), a living attenuated strain of Mycobacterium bovis, was found to induce tumor regression by stimulating cell-mediated immunity following a localized and self-limiting infection. We evaluated these two immune stimulants in combination with melanoma with the aim of developing a more effective immunotherapy and to assess toxicity. In this phase I study, patients with histologically confirmed stage III/IV metastatic melanoma received IL BCG injection followed by up to four cycles of intravenous ipilimumab (anti-CTLA-4) ( number NCT01838200). The trial was discontinued following treatment of the first five patients as the two patients receiving the escalation dose of BCG developed high-grade immune-related adverse events (irAEs) typical of ipilimumab monotherapy. These irAEs were characterized in both patients by profound increases in the repertoire of autoantibodies directed against both self- and cancer antigens. Interestingly, the induced autoantibodies were detected at time points that preceded the development of symptomatic toxicity. There was no overlap in the antigen specificity between patients and no evidence of clinical responses. Efforts to increase response rates through the use of novel immunotherapeutic combinations may be associated with higher rates of irAEs, thus the imperative to identify biomarkers of toxicity remains strong. While the small patient numbers in this trial do not allow for any conclusive evidence of predictive biomarkers, the observed changes warrant further examination of autoantibody repertoires in larger patient cohorts at risk of developing irAEs during their course of treatment. In summary, dose escalation of IL BCG followed by ipilimumab therapy was not well tolerated in advanced melanoma patients and showed no evidence of clinical benefit. Measuring autoantibody responses may provide early means for identifying patients at risk from developing severe irAEs during cancer immunotherapy.