Genetic basis for clinical response to CTLA-4 blockade in melanoma.
Genetic basis for clinical response to CTLA-4 blockade in melanoma.
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DOI：
10.1056/nejmoa1406498
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发表时间：
2014-12-04
期刊：
影响因子：
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通讯作者：
Chan TA
中科院分区：
文献类型：
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作者：
Snyder A;Makarov V;Merghoub T;Yuan J;Zaretsky JM;Desrichard A;Walsh LA;Postow MA;Wong P;Ho TS;Hollmann TJ;Bruggeman C;Kannan K;Li Y;Elipenahli C;Liu C;Harbison CT;Wang L;Ribas A;Wolchok JD;Chan TA
免疫检查点抑制剂是有效的癌症治疗方法，但临床获益的分子决定因素尚不清楚。伊匹单抗和曲美木单抗是针对细胞毒性T淋巴细胞抗原4（CTLA-4）的抗体。抗CTLA-4治疗可延长黑色素瘤患者的总生存期。CTLA-4阻断剂激活T细胞并使它们能够破坏肿瘤细胞。我们从接受伊匹单抗或曲美木单抗治疗的黑色素瘤患者中获得肿瘤组织。对肿瘤和匹配的血液样品进行全外显子组测序。表征了体细胞突变和由这些突变产生的候选新抗原。测试新抗原肽活化来自伊匹单抗治疗的患者的淋巴细胞的能力。使用大规模平行测序对来自64名接受CTLA-4阻断治疗的患者的恶性黑素瘤外显子组进行表征。发现集包括11例获得长期临床获益的患者和14例获得最小获益或无获益的患者。突变负荷与临床获益程度相关（P = 0.01），但单独不足以预测获益。使用全基因组体细胞新表位分析和患者特异性HLA分型，我们确定了每个患者的候选肿瘤新抗原。我们阐明了特异性存在于对CTLA-4阻断具有强烈反应的肿瘤中的新抗原景观。我们在第二组39例接受抗CTLA-4抗体治疗的黑色素瘤患者中验证了这一特征。预测的新抗原活化来自用伊匹单抗治疗的患者的T细胞。这些发现定义了从黑色素瘤中CTLA-4阻断获益的遗传基础，并为检查正在考虑使用抗CTLA-4药物的患者的外显子组提供了依据。（由Frederick Adler Fund和其他人资助。
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 neo-antigen 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.)