Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma
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 an...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Springer Science and Business Media LLC
2020
|
| Online Access: | https://hdl.handle.net/1721.1/125847 |
| _version_ | 1826206360038014976 |
|---|---|
| author | Liu, David V. Liu, Derek Jerby-Arnon, Livnat Vokes, Natalie I. Margolis, Claire A. Conway, Jake He, Meng Xiao Elmarakeby, Haitham Dietlein, Felix Miao, Diana Tracy, Adam Izar, Benjamin Regev, Aviv Van Allen, Eliezer M. |
| author2 | Broad Institute of MIT and Harvard |
| author_facet | Broad Institute of MIT and Harvard Liu, David V. Liu, Derek Jerby-Arnon, Livnat Vokes, Natalie I. Margolis, Claire A. Conway, Jake He, Meng Xiao Elmarakeby, Haitham Dietlein, Felix Miao, Diana Tracy, Adam Izar, Benjamin Regev, Aviv Van Allen, Eliezer M. |
| author_sort | Liu, David V. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T13:28:15Z |
| format | Article |
| id | mit-1721.1/125847 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T13:28:15Z |
| publishDate | 2020 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1258472022-10-01T15:28:53Z Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma Liu, David V. Liu, Derek Jerby-Arnon, Livnat Vokes, Natalie I. Margolis, Claire A. Conway, Jake He, Meng Xiao Elmarakeby, Haitham Dietlein, Felix Miao, Diana Tracy, Adam Izar, Benjamin Regev, Aviv Van Allen, Eliezer M. Broad Institute of MIT and Harvard 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. 2020-06-17T18:36:59Z 2020-06-17T18:36:59Z 2019-12 2020-01-28T19:15:01Z Article http://purl.org/eprint/type/JournalArticle 1078-8956 1546-170X https://hdl.handle.net/1721.1/125847 Liu, David, et al., "Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma." Nature Medicine 25 (Dec. 2019): p. 1916-27 doi 10.1038/s41591-019-0654-5 ©2019 Author(s) en 10.1038/s41591-019-0654-5 Nature Medicine Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Springer Science and Business Media LLC Nature |
| spellingShingle | Liu, David V. Liu, Derek Jerby-Arnon, Livnat Vokes, Natalie I. Margolis, Claire A. Conway, Jake He, Meng Xiao Elmarakeby, Haitham Dietlein, Felix Miao, Diana Tracy, Adam Izar, Benjamin Regev, Aviv Van Allen, Eliezer M. Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma |
| title | Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma |
| title_full | Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma |
| title_fullStr | Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma |
| title_full_unstemmed | Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma |
| title_short | Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma |
| title_sort | integrative molecular and clinical modeling of clinical outcomes to pd1 blockade in patients with metastatic melanoma |
| url | https://hdl.handle.net/1721.1/125847 |
| work_keys_str_mv | AT liudavidv integrativemolecularandclinicalmodelingofclinicaloutcomestopd1blockadeinpatientswithmetastaticmelanoma AT liuderek integrativemolecularandclinicalmodelingofclinicaloutcomestopd1blockadeinpatientswithmetastaticmelanoma AT jerbyarnonlivnat integrativemolecularandclinicalmodelingofclinicaloutcomestopd1blockadeinpatientswithmetastaticmelanoma AT vokesnataliei integrativemolecularandclinicalmodelingofclinicaloutcomestopd1blockadeinpatientswithmetastaticmelanoma AT margolisclairea integrativemolecularandclinicalmodelingofclinicaloutcomestopd1blockadeinpatientswithmetastaticmelanoma AT conwayjake integrativemolecularandclinicalmodelingofclinicaloutcomestopd1blockadeinpatientswithmetastaticmelanoma AT hemengxiao integrativemolecularandclinicalmodelingofclinicaloutcomestopd1blockadeinpatientswithmetastaticmelanoma AT elmarakebyhaitham integrativemolecularandclinicalmodelingofclinicaloutcomestopd1blockadeinpatientswithmetastaticmelanoma AT dietleinfelix integrativemolecularandclinicalmodelingofclinicaloutcomestopd1blockadeinpatientswithmetastaticmelanoma AT miaodiana integrativemolecularandclinicalmodelingofclinicaloutcomestopd1blockadeinpatientswithmetastaticmelanoma AT tracyadam integrativemolecularandclinicalmodelingofclinicaloutcomestopd1blockadeinpatientswithmetastaticmelanoma AT izarbenjamin integrativemolecularandclinicalmodelingofclinicaloutcomestopd1blockadeinpatientswithmetastaticmelanoma AT regevaviv integrativemolecularandclinicalmodelingofclinicaloutcomestopd1blockadeinpatientswithmetastaticmelanoma AT vanalleneliezerm integrativemolecularandclinicalmodelingofclinicaloutcomestopd1blockadeinpatientswithmetastaticmelanoma |