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.
| Original language | English |
|---|---|
| Journal | Nature Medicine |
| Volume | 25 |
| Issue number | 12 |
| Pages (from-to) | 1916-1927 |
| Number of pages | 12 |
| ISSN | 1078-8956 |
| DOIs | |
| Publication status | Published - 01.12.2019 |
Funding
The authors thank the active investigators A. Gesierich (University Hospital Würzburg), J.C. Hassel (NCT Heidelberg), C. Pföhler (Saarland University Medical Center), E. Dabrowski (Ludwigshafen Medical Center), L.A. Schneider (University Medical Center Ulm), C. Weishaupt (University Hospital of Münster), K.G. Griewank (University Hospital Essen), E. Hadaschik (University Hospital Essen), G. Kyriakakis (Laikon General Hospital), F. Meier (NCT Dresden), M.H. Geukes Foppen (The Netherlands Cancer Institute), R. Dummer (University Hospital Zürich), E. Bräunlein (Technical University Munich) and M. Boxberg (Technical University Munich) for providing additional patient samples and clinical data. The authors also thank A. Giobbie-Hurder (Dana-Farber Cancer Institute) and J. Weirather (Dana-Farber Cancer Institute) for useful discussions regarding statistical testing. This work was supported by the Adelson Medical Research Foundation (L.G.), the Conquer Cancer Foundation (David Liu), the Society for Immunotherapy of Cancers (David Liu), the Damon Runyon Cancer Research Foundation (David Liu), the BroadNext10 (E.M.V.), the National Institutes of Health (K08 CA234458 (David Liu), R01 CA227388 (E.M.V.), U01 CA233100 (E.M.V.), T32 GM008313 (M.X.H.)), the Deutsche Forschungsgemeinschaft (German Research Foundation), SCHA 422/17-1, PA 2376/1-1 and HO 6389/2-1 (KFO 337; D.S, A.P.) and National Science Foundation Graduate Research Fellowship Program DGE1144152 (M.X.H.). David Liu reports funding by a postdoctoral fellowship from the Society for Immunotherapy of Cancers, which is funded in part by an educational grant from Bristol-Meyers Squibb (BMS). BMS has had no input into the conception, conduct or reporting of the submitted work. B.S. is on the advisory board or has received honoraria from Incyte, Novartis, Roche, BMS and Merck Sharp & Dohme (MSD), research funding from Pierre-Fabre Pharmaceuticals, BMS and MSD and travel support from Novartis, Roche, BMS, Pierre-Fabre Pharmaceuticals, MSD and Amgen, outside the scope of the submitted work. D.S. reports grants, personal fees and nonfinancial support from BMS, personal fees and nonfinancial support from Roche, grants, personal fees and nonfinancial support from Novartis, nonfinancial support from Regeneron, personal fees from Sanofi, personal fees and nonfinancial support from MSD, personal fees and nonfinancial support from Amgen, personal fees and nonfinancial support from 4SC, personal fees and nonfinancial support from Merck-EMD, personal fees from Array, personal fees and nonfinancial support from Pierre-Fabre, personal fees and nonfinancial support from Philogen, personal fees and nonfinancial support from Incyte and personal fees from Pfizer, outside the scope of the submitted work. E.M.V.A. reports advisory relationships and consulting with Tango Therapeutics, Genome Medical, Invitae, Illumina and Ervaxx; research support from Novartis and BMS; equity in Tango Therapeutics, Genome Medical, Syapse, Ervaxx and Microsoft; and travel reimbursement from Roche and Genentech, outside the submitted work. S.G. reports personal fees from MSD, personal fees from BMS, personal fees from Novartis and personal fees from Roche, outside the scope of the submitted work. L.Z. reports personal fees and others from BMS, personal fees and others from Novartis, personal fees and others from Pierre-Fabre, personal fees and others from MSD, personal fees from Roche, other fees from Amgen and personal fees from Sanofi, outside the scope of the submitted work. F.K. reports personal fees from Amgen, personal fees from BMS, grants and personal fees from Novartis, personal fees from Roche, personal fees from MSD and personal fees from Merck, outside the submitted work. J.U. reports personal fees and nonfinancial support from Amgen, personal fees and nonfinancial support from BMS, personal fees and nonfinancial support from MSD, personal fees and nonfinancial support from Novartis, personal fees and nonfinancial support from Pierre-Fabre, and personal fees and nonfinancial support from Roche, outside the scope of the submitted work. H.G. reports grants and personal fees from BMS, grants and personal fees from Roche, grants and personal fees from MSD, grants and personal fees from Novartis, personal fees from Amgen and personal fees from Pierre-Fabre, outside the scope of the submitted work. R.G. reports personal fees and nonfinancial support from BMS, personal fees and nonfinancial support from Roche Pharma, personal fees and nonfinancial support from Merck Serono, grants, personal fees and nonfinancial support from Amgen, personal fees and nonfinancial support from Pierre-Fabre, personal fees and nonfinancial support from Sanofi Regeneron, personal fees from MSD, grants, personal fees and nonfinancial support from Novartis, personal fees and nonfinancial support from Almirall Hermal, grants and personal fees from Pfizer, personal fees from LEO, personal fees from AstraZeneca, personal fees from Sun Pharma, personal fees from 4SC and grants from Johnson & Johnson, outside the scope of the submitted work. I.S. reports grants and personal fees from Novartis, grants from Pfizer, personal fees from Roche, personal fees BMS and personal fees from MSD, outside the scope of the submitted work. C.L. reports personal fees from Roche, personal fees from Novartis, personal fees from Pierre-Fabre, personal fees from BMS, personal fees from MSD, personal fees from Amgen and personal fees from Idera and Sun Pharma, outside the scope of the submitted work. S.G. reports personal fees from BMS, personal fees from MSD and personal fees from Merck KGaA, outside the scope of the submitted work. E.L. reports personal fees and others from Amgen, personal fees and others from BMS, personal fees and others from MSD, personal fees and others from Novartis, personal fees and others from Roche, personal fees from medac, personal fees from Janssen, other fees from Actelion and other fees from Pierre-Fabre, outside the scope of the submitted work. A.K. reports grants from BMS and Kiadis, personal fees from BMS, Sanofi, Novartis, Roche, Vaccibody and nonfinancial support from Sanofi and BMS, outside the scope of the submitted work. C.B. reports personal fees from BMS, MSD, Roche, Novartis, GSK, Pfizer, Lilly, Pierre-Fabre and GenMab and grants from BMS, Novartis and NanoString, outside the scope of the submitted work. S.H. reports personal fees from Novartis, personal fees from BMS, personal fees from Amgen, personal fees from Pierre-Fabre and personal fees from Roche, outside the scope of the submitted work. B.W. reports grants and personal fees from Philogen, personal fees from Curevac, grants and personal fees from MSD, grants and personal fees from BMS and personal fees from GSK, outside the scope of the submitted work. R.R. reports personal fees from Novartis, personal fees and nonfinancial support from Amgen and nonfinancial support from BMS, outside the scope of the submitted work. D.v.B., A.S. and A.P. have nothing to disclose.
