Targeted Next Generation Sequencing Identifies Markers of Response to PD-1 Blockade.
Targeted Next Generation Sequencing Identifies Markers of Response to PD-1 Blockade.
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DOI：
10.1158/2326-6066.cir-16-0143
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发表时间：
2016-11
影响因子：
10.1
通讯作者：
Lovly CM
中科院分区：
文献类型：
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作者：
Johnson DB;Frampton GM;Rioth MJ;Yusko E;Xu Y;Guo X;Ennis RC;Fabrizio D;Chalmers ZR;Greenbowe J;Ali SM;Balasubramanian S;Sun JX;He Y;Frederick DT;Puzanov I;Balko JM;Cates JM;Ross JS;Sanders C;Robins H;Shyr Y;Miller VA;Stephens PJ;Sullivan RJ;Sosman JA;Lovly CM
治疗性抗体阻止了编程死亡-1及其配体（PD-1/PD-L1）诱导黑色素瘤患者的次要部分的持久反应。 NGS）在临床中可用的面板与黑色素瘤中对抗PD-1的反应相关。基于236-315个基因的基于捕获的NG和T-Cell接收器（TCR）测序对两个中心的初始和验证队列，对抗PD-1/PD-L1的反应。 ）45.6 vs. 3.9突变/mb; p = 0.003），与非反应率相比与中间体和低突变载荷组相比，NF1突变具有高突变载荷（中位数62.7突变/MB）和高反应率（74％）在这些档案样本中，TCR的载荷量较低，在NGS平台中的315个基因中的反应与整个外显子组中检测到的反应密切相关癌症基因组样品，但与临床上的NGS平台确定的结论无关。 PD-1/PD-L1。
Therapeutic antibodies blocking programmed death-1 and its ligand (PD-1/PD-L1) induce durable responses in a substantial fraction of melanoma patients. We sought to determine whether the number and/or type of mutations identified using a next generation sequencing (NGS) panel available in the clinic were correlated with response to anti–PD-1 in melanoma. Using archival melanoma samples from anti–PD-1/PD-L1-treated patients, we performed hybrid capture-based NGS on 236–315 genes and T-cell receptor (TCR) sequencing on initial and validation cohorts from two centers. Patients who responded to anti–PD-1/PD-L1 had higher mutational loads in an initial cohort (median 45.6 vs. 3.9 mutations/MB; P = 0.003), and a validation cohort (37.1 vs. 12.8 mutations/MB; P = 0.002) compared to nonresponders. Response rate, progression-free survival, and overall survival was superior in the high, compared to intermediate and low, mutation load groups. Melanomas with NF1 mutations harbored high mutational loads (median 62.7 mutations/MB) and high response rates (74%) whereas BRAF/NRAS/NF1 wild-type melanomas had a lower mutational load. In these archival samples, TCR clonality did not predict response. Mutation numbers in the 315 genes in the NGS platform strongly correlated with those detected by whole exome sequencing in The Cancer Genome Atlas samples, but was not associated with survival. In conclusion, mutational load, as determined by an NGS platform available in the clinic, effectively stratified patients by likelihood of response. This approach may provide a clinically feasible predictor of response to anti–PD-1/PD-L1.