Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden.
Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden.
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DOI：
10.1186/s40425-018-0344-8
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发表时间：
2018-05-09
影响因子：
10.9
通讯作者：
Ernstoff MS
中科院分区：
文献类型：
--
作者：
Morrison C;Pabla S;Conroy JM;Nesline MK;Glenn ST;Dressman D;Papanicolau-Sengos A;Burgher B;Andreas J;Giamo V;Qin M;Wang Y;Lenzo FL;Omilian A;Bshara W;Zibelman M;Ghatalia P;Dragnev K;Shirai K;Madden KG;Tafe LJ;Shah N;Kasuganti D;de la Cruz-Merino L;Araujo I;Saenger Y;Bogardus M;Villalona-Calero M;Diaz Z;Day R;Eisenberg M;Anderson SM;Puzanov I;Galluzzi L;Gardner M;Ernstoff MS
免疫检查点抑制剂（ICI）改变了黑色素瘤的临床管理。然而，并非所有患者都有反应，目前的生物标志物包括PD-L1和突变负荷显示出不完全的预测性能。复杂生物标志物的临床有效性和实用性尚未在黑色素瘤中进行研究。评估了8家机构的皮肤转移性黑色素瘤患者的PD-L1表达、CD 8 + T细胞浸润模式、突变负荷和394免疫转录物表达。在FDA批准ICI之前接受治疗的94例患者（历史对照）和接受ICI治疗的137例患者中，评估了PD-L1 IHC和突变负荷与总生存期（OS）的相关性。无监督分析揭示了具有单独应答率的不同免疫簇。然后将该全面的免疫分析数据进行整合，以基于缓解标准（RECIST v.1.1）生成连续缓解评分（RS）。RS使用单个机构培训队列（n = 48）开发，随后在单独的8个机构验证队列（n = 29）中进行测试，以模拟真实世界的临床场景。在ICI治疗患者中，PD-L1阳性≥1%与缓解和OS相关，但表现出有限的预测性能。高突变负荷与ICI治疗患者的缓解相关，但与OS无关。使用RS进行的综合免疫分析显示，与PD-L1 IHC（34.25%）和肿瘤突变负荷（32.5%）相比，其灵敏度（72.2%）更高，但特异性相似。在本研究中，与PD-L1 IHC和肿瘤突变负荷相比，在有限的黑色素瘤队列中从综合免疫分析中得出的缓解评分显示出预测性能改善。本文的在线版本（10.1186/s40425-018-0344-8）包含补充材料，可供授权用户使用。
Immune checkpoint inhibitors (ICIs) have changed the clinical management of melanoma. However, not all patients respond, and current biomarkers including PD-L1 and mutational burden show incomplete predictive performance. The clinical validity and utility of complex biomarkers have not been studied in melanoma. Cutaneous metastatic melanoma patients at eight institutions were evaluated for PD-L1 expression, CD8+ T-cell infiltration pattern, mutational burden, and 394 immune transcript expression. PD-L1 IHC and mutational burden were assessed for association with overall survival (OS) in 94 patients treated prior to ICI approval by the FDA (historical-controls), and in 137 patients treated with ICIs. Unsupervised analysis revealed distinct immune-clusters with separate response rates. This comprehensive immune profiling data were then integrated to generate a continuous Response Score (RS) based upon response criteria (RECIST v.1.1). RS was developed using a single institution training cohort (n = 48) and subsequently tested in a separate eight institution validation cohort (n = 29) to mimic a real-world clinical scenario. PD-L1 positivity ≥1% correlated with response and OS in ICI-treated patients, but demonstrated limited predictive performance. High mutational burden was associated with response in ICI-treated patients, but not with OS. Comprehensive immune profiling using RS demonstrated higher sensitivity (72.2%) compared to PD-L1 IHC (34.25%) and tumor mutational burden (32.5%), but with similar specificity. In this study, the response score derived from comprehensive immune profiling in a limited melanoma cohort showed improved predictive performance as compared to PD-L1 IHC and tumor mutational burden. The online version of this article (10.1186/s40425-018-0344-8) contains supplementary material, which is available to authorized users.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
7.3
作者：
Efremova M;Finotello F;Rieder D;Trajanoski Z
通讯作者：
Trajanoski Z
DOI：
10.1056/nejmoa1709684
发表时间：
2017-10-05
期刊：
The New England journal of medicine
影响因子：
--
作者：
Wolchok JD;Chiarion-Sileni V;Gonzalez R;Rutkowski P;Grob JJ;Cowey CL;Lao CD;Wagstaff J;Schadendorf D;Ferrucci PF;Smylie M;Dummer R;Hill A;Hogg D;Haanen J;Carlino MS;Bechter O;Maio M;Marquez-Rodas I;Guidoboni M;McArthur G;Lebbé C;Ascierto PA;Long GV;Cebon J;Sosman J;Postow MA;Callahan MK;Walker D;Rollin L;Bhore R;Hodi FS;Larkin J
通讯作者：
Larkin J
DOI：
10.1038/nrclinonc.2017.88
发表时间：
2017-11
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Nishino M;Ramaiya NH;Hatabu H;Hodi FS
通讯作者：
Hodi FS
DOI：
10.1056/nejmoa1504030
发表时间：
2015-07-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Larkin J;Chiarion-Sileni V;Gonzalez R;Grob JJ;Cowey CL;Lao CD;Schadendorf D;Dummer R;Smylie M;Rutkowski P;Ferrucci PF;Hill A;Wagstaff J;Carlino MS;Haanen JB;Maio M;Marquez-Rodas I;McArthur GA;Ascierto PA;Long GV;Callahan MK;Postow MA;Grossmann K;Sznol M;Dreno B;Bastholt L;Yang A;Rollin LM;Horak C;Hodi FS;Wolchok JD
通讯作者：
Wolchok JD