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Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade
Science ( IF 44.7 ) Pub Date : 2017-06-08 , DOI: 10.1126/science.aan6733
Dung T Le 1, 2, 3 , Jennifer N Durham 1, 2, 3 , Kellie N Smith 1, 3 , Hao Wang 3 , Bjarne R Bartlett 2, 4 , Laveet K Aulakh 2, 4 , Steve Lu 2, 4 , Holly Kemberling 3 , Cara Wilt 3 , Brandon S Luber 3 , Fay Wong 2, 4 , Nilofer S Azad 1, 3 , Agnieszka A Rucki 1, 3 , Dan Laheru 3 , Ross Donehower 3 , Atif Zaheer 5 , George A Fisher 6 , Todd S Crocenzi 7 , James J Lee 8 , Tim F Greten 9 , Austin G Duffy 9 , Kristen K Ciombor 10 , Aleksandra D Eyring 11 , Bao H Lam 11 , Andrew Joe 11 , S Peter Kang 11 , Matthias Holdhoff 3 , Ludmila Danilova 1, 3 , Leslie Cope 1, 3 , Christian Meyer 3 , Shibin Zhou 1, 3, 4 , Richard M Goldberg 12 , Deborah K Armstrong 3 , Katherine M Bever 3 , Amanda N Fader 13 , Janis Taube 1, 3 , Franck Housseau 1, 3 , David Spetzler 14 , Nianqing Xiao 14 , Drew M Pardoll 1, 3 , Nickolas Papadopoulos 3, 4 , Kenneth W Kinzler 3, 4 , James R Eshleman 15 , Bert Vogelstein 1, 3, 4 , Robert A Anders 1, 3, 15 , Luis A Diaz 1, 2, 3
Affiliation  

Predicting responses to immunotherapy Colon cancers with loss-of-function mutations in the mismatch repair (MMR) pathway have favorable responses to PD-1 blockade immunotherapy. In a phase 2 clinical trial, Le et al. showed that treatment success is not just limited to colon cancer (see the Perspective by Goswami and Sharma). They found that a wide range of different cancer types with MMR deficiency also responded to PD-1 blockade. The trial included some patients with pancreatic cancer, which is one of the deadliest forms of cancer. The clinical trial is still ongoing, and around 20% of patients have so far achieved a complete response. MMR deficiency appears to be a biomarker for predicting successful treatment outcomes for several solid tumors and indicates a new therapeutic option for patients harboring MMR-deficient cancers. Science, this issue p. 409; see also p. 358 A pan-cancer biomarker is identified that can predict successful response to cancer immunotherapy in human patients. The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor–1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair–deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair–deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin.

中文翻译:

错配修复缺陷预测实体瘤对 PD-1 阻断的反应

预测对免疫疗法的反应在错配修复 (MMR) 通路中具有功能丧失突变的结肠癌对 PD-1 阻断免疫疗法有良好的反应。在 2 期临床试验中,Le 等人。表明治疗成功不仅限于结肠癌(参见 Goswami 和 Sharma 的观点)。他们发现,具有 MMR 缺陷的多种不同癌症类型也对 PD-1 阻断剂有反应。该试验包括一些胰腺癌患者,胰腺癌是最致命的癌症之一。临床试验仍在进行中,目前约有 20% 的患者获得了完全缓解。MMR 缺陷似乎是预测几种实体瘤成功治疗结果的生物标志物,并为患有 MMR 缺陷癌症的患者提供了一种新的治疗选择。科学,这个问题p。409;另见 p. 358 鉴定出一种泛癌生物标志物,可以预测人类患者对癌症免疫疗法的成功反应。错配修复缺陷的癌症基因组包含异常多的体细胞突变。在一项概念验证研究中,我们之前表明,具有错配修复缺陷的结直肠癌对使用程序性死亡受体-1 (PD-1) 抗体进行的免疫检查点封锁敏感。我们现在扩大了这项研究,以评估 PD-1 阻断剂对 12 种不同肿瘤类型的晚期错配修复缺陷癌症患者的疗效。53% 的患者观察到客观放射学反应,21% 的患者达到完全反应。反应是持久的,中位无进展生存期和总生存期仍未达到。对一名有反应的患者进行的功能分析表明,新抗原特异性 T 细胞克隆在体内快速扩增,这些克隆对肿瘤中发现的突变新肽有反应。这些数据支持这样的假设,即错配修复缺陷癌症中的大部分突变新抗原使它们对免疫检查点封锁敏感,而不管癌症的起源组织如何。
更新日期:2017-06-08
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