Liu, David and Schilling, Bastian and Liu, Derek and Sucker, Antje and Livingstone, Elisabeth and Jerby-Amon, Livnat and Zimmer, Lisa and Gutzmer, Ralf and Satzger, Imke and Loquai, Carmen and Grabbe, Stephan and Vokes, Natalie and Margolis, Claire A. and Conway, Jake and He, Meng Xiao and Elmarakeby, Haitham and Dietlein, Felix and Miao, Diana and Tracy, Adam and Gogas, Helen and Goldinger, Simone M. and Utikal, Jochen and Blank, Christian U. and Rauschenberg, Ricarda and von Bubnoff, Dagmar and Krackhardt, Angela and Weide, Benjamin and Haferkamp, Sebastian and Kiecker, Felix and Izar, Ben and Garraway, Levi and Regev, Aviv and Flaherty, Keith and Paschen, Annette and Van Allen, Eliezer M. and Schadendorf, Dirk (2019) Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma. NATURE MEDICINE, 25 (12). pp. 1916-1927. ISSN 1078-8956, 1546-170X
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PD-1 BLOCKADE; OPEN-LABEL; CTLA-4 BLOCKADE; RESISTANCE; MUTATIONS; PEMBROLIZUMAB; IPILIMUMAB; SIGNATURES; NIVOLUMAB; MULTICENTER; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Dermatologie und Venerologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Mar 2020 08:13 |
| Last Modified: | 23 Mar 2020 08:13 |
| URI: | https://pred.uni-regensburg.de/id/eprint/25759 |
Actions (login required)
 |
View Item |
