小柯机器人

德国癌症研究中心Dirk Schadendorf、美国丹娜-法伯癌症研究院Eliezer M. Van Allen等研究人员合作建立了转移性黑素瘤患者对PD1治疗的响应模型。相关论文2019年12月2日在线发表于《自然—医学》。

研究人员表示，免疫检查点封锁（ICB）已在许多类型的肿瘤中显示出疗效，但抗PD1 ICB反应性的预测因子尚未完全定义。

研究人员分析了用抗PD1 ICB治疗的黑色素瘤患者（n=144）的临床注释队列，并对治疗前肿瘤进行了全外显子组和全转录组测序。研究人员发现黑素瘤亚型混淆了作为反应预测因子的肿瘤突变负担，而多个新的基因组和转录组特征预测了选择性反应，包括与MHC-I和MHC-II抗原呈递相关的特征。此外，与未接触过ICB的肿瘤相比，先前的抗CTLA4 ICB暴露与不同的反应预测因子相关，这表明先前接触过抗CTLA4 ICB的选择性免疫效应。最后，研究人员开发了结合临床、基因组和转录组学特征的简约模型，从而预测个体肿瘤中抗PD1 ICB的内在抗性，并在较小的独立研究组中进行了验证（受综合数据的限制）。概括地说，研究人员提出了一个框架，其可发现预测特征并建立ICB治疗反应模型。

附：英文原文

Title: Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma

Author: David Liu, Bastian Schilling, Derek Liu, Antje Sucker, Elisabeth Livingstone, Livnat Jerby-Amon, Lisa Zimmer, Ralf Gutzmer, Imke Satzger, Carmen Loquai, Stephan Grabbe, Natalie Vokes, Claire A. Margolis, Jake Conway, Meng Xiao He, Haitham Elmarakeby, Felix Dietlein, Diana Miao, Adam Tracy, Helen Gogas, Simone M. Goldinger, Jochen Utikal, Christian U. Blank, Ricarda Rauschenberg, Dagmar von Bubnoff, Angela Krackhardt, Benjamin Weide, Sebastian Haferkamp, Felix Kiecker, Ben Izar, Levi Garraway, Aviv Regev, Keith Flaherty, Annette Paschen, Eliezer M. Van Allen, Dirk Schadendorf

Issue&Volume: 2019-12-02

Abstract: Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n=144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.

DOI: 10.1038/s41591-019-0654-5

Source: https://www.nature.com/articles/s41591-019-0654-5

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex