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Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma

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
出处
期刊:The New England Journal of Medicine [Massachusetts Medical Society]
卷期号:371 (23): 2189-2199 被引量:3569
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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