银耳霉素
医学
封锁
CTLA-4号机组
黑色素瘤
外显子组测序
易普利姆玛
外显子组
免疫学
癌症免疫疗法
免疫疗法
无容量
免疫检查点
肿瘤科
癌症研究
T细胞
内科学
免疫系统
突变
生物
遗传学
受体
基因
作者
Alexandra Snyder,Vladimir Makarov,Taha Merghoub,Jianda Yuan,Jesse M. Zaretsky,Alexis Desrichard,Logan A. Walsh,Michael A. Postow,Phillip Wong,Teresa S. Ho,Travis J. Hollmann,Cameron Bruggeman,Kasthuri Kannan,Yanyun Li,Ceyhan Elipenahli,Cailian Liu,Christopher Harbison,Lisu Wang,Antoni Ribas,Jedd D. Wolchok,Timothy A. Chan
标识
DOI:10.1056/nejmoa1406498
摘要
Immune checkpoint inhibitors are effective cancer treatments, but molecular determinants of clinical benefit are unknown. Ipilimumab and tremelimumab are antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4). Anti-CTLA-4 treatment prolongs overall survival in patients with melanoma. CTLA-4 blockade activates T cells and enables them to destroy tumor cells.We obtained tumor tissue from patients with melanoma who were treated with ipilimumab or tremelimumab. Whole-exome sequencing was performed on tumors and matched blood samples. Somatic mutations and candidate neoantigens generated from these mutations were characterized. Neoantigen peptides were tested for the ability to activate lymphocytes from ipilimumab-treated patients.Malignant melanoma exomes from 64 patients treated with CTLA-4 blockade were characterized with the use of massively parallel sequencing. A discovery set consisted of 11 patients who derived a long-term clinical benefit and 14 patients who derived a minimal benefit or no benefit. Mutational load was associated with the degree of clinical benefit (P=0.01) but alone was not sufficient to predict benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA typing, we identified candidate tumor neoantigens for each patient. We elucidated a neoantigen landscape that is specifically present in tumors with a strong response to CTLA-4 blockade. We validated this signature in a second set of 39 patients with melanoma who were treated with anti-CTLA-4 antibodies. Predicted neoantigens activated T cells from the patients treated with ipilimumab.These findings define a genetic basis for benefit from CTLA-4 blockade in melanoma and provide a rationale for examining exomes of patients for whom anti-CTLA-4 agents are being considered. (Funded by the Frederick Adler Fund and others.).
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