Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma.
Junfei Zhao,Andrew X. Chen,Robyn D. Gartrell,Andrew M. Silverman,Luis Aparicio,Tim Chu,Darius Bordbar,David Shan,Jorge Samanamud,Aayushi Mahajan,Ioan Filip,Rose Orenbuch,Morgan Goetz,Jonathan T. Yamaguchi,Michael Cloney,Craig Horbinski,Rimas V. Lukas,Jeffrey Raizer,Ali I Rae,Jinzhou Yuan,Peter Canoll,Jeffrey N. Bruce,Yvonne M. Saenger,Peter A. Sims,Fabio M. Iwamoto,Adam M. Sonabend,Raul Rabadan +26 more
TLDR
This study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor’s clonal evolution during treatment.Abstract:
Immune checkpoint inhibitors have been successful across several tumor types; however, their efficacy has been uncommon and unpredictable in glioblastomas (GBM), where <10% of patients show long-term responses. To understand the molecular determinants of immunotherapeutic response in GBM, we longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors (nivolumab or pembrolizumab). Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of MAPK pathway alterations (PTPN11, BRAF) in responders. Responsive tumors were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumor microenvironment profiles. Our study shows that clinical response to anti-PD-1 immunotherapy in GBM is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumor’s clonal evolution during treatment. Genomic, transcriptomic, and microenvironmental analyses of samples from patients with glioblastoma treated with nivolumab or pembrolizumab identifies features associated with treatment response that may help in refining patient stratification.read more
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The somatic genomic landscape of glioblastoma
Cameron Brennan,Roel G.W. Verhaak,Aaron McKenna,Benito Campos,Houtan Noushmehr,Sofie R. Salama,Siyuan Zheng,Debyani Chakravarty,J. Zachary Sanborn,Samuel H. Berman,Rameen Beroukhim,Brady Bernard,Chang-Jiun Wu,Giannicola Genovese,Ilya Shmulevich,Jill S. Barnholtz-Sloan,Lihua Zou,Rahulsimham Vegesna,Sachet A. Shukla,Giovanni Ciriello,W. K. Yung,Wei Zhang,Carrie Sougnez,Tom Mikkelsen,Kenneth Aldape,Darell D. Bigner,Erwin G. Van Meir,Michael D. Prados,Andrew E. Sloan,Keith L. Black,Jennifer M. Eschbacher,Gaetano Finocchiaro,William A. Friedman,David W. Andrews,Abhijit Guha,Mary Iacocca,Brian P. O'Neil,Greg Foltz,Jerome Myers,Daniel J. Weisenberger,Robert Penny,Raju Kucherlapati,Charles M. Perou,D. Neil Hayes,Richard A. Gibbs,Marco A. Marra,Gordon B. Mills,Eric S. Lander,Paul T. Spellman,Richard K. Wilson,Chris Sander,John N. Weinstein,Matthew Meyerson,Stacey Gabriel,Peter W. Laird,David Haussler,Gad Getz,Lynda Chin +57 more
TL;DR: In this article, the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs) was described, including several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA.
Journal ArticleDOI
Mechanisms of immunotherapy resistance: lessons from glioblastoma.
TL;DR: The mechanisms of immunotherapy resistance in GBM are reviewed and how insights into GBM–immune system interactions might inform the next generation of immunotherapeutics for GBM and other resistant pathologies are discussed.
Journal ArticleDOI
Advances in the development of personalized neoantigen-based therapeutic cancer vaccines
Eryn Blass,Patrick A. Ott +1 more
TL;DR: In this article, the authors provide an overview of the complex process that is necessary to generate a personalized neoantigen vaccine, review the types of vaccine-induced T cells that are found within tumours and outline strategies to enhance the T cell responses.
Additional file 1: Figures S1â S25. of Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures
Yasin ĹenbabaoÄlu,Ron S. Gejman,Andrew G. Winer,Ming Liu,Eliezer M. Van Allen,Guillermo de Velasco,Diana Miao,Irina Ostrovnaya,Esther Drill,Augustin Luna,Nils Weinhold,William E. Lee,Brandon Manley,Danny N. Khalil,Samuel D. Kaffenberger,Ying-Bei Chen,Ludmila Danilova,Martin H. Voss,Jonathan A. Coleman,Paul Russo,Victor R. Reuter,Timothy A. Chan,Emily H. Y. Cheng,David A. Scheinberg,Ming Li,T.K. Choueiri,James Hsieh,Chris Sander,A.A. Hakimi +28 more
TL;DR: It is observed that the immunogenicity of ccRCC tumors cannot be explained by mutation load or neo-antigen load, but is highly correlated with MHC class I antigen presenting machinery expression (APM).
Journal ArticleDOI
Brain immunology and immunotherapy in brain tumours
TL;DR: How advances in the understanding of the immune system within the brain have implications for the successful implementation of immunotherapy to treat brain tumours is discussed, despite challenges such as effective delivery, target specificity and intratumour heterogeneity.
References
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Journal ArticleDOI
Fast and accurate short read alignment with Burrows–Wheeler transform
Heng Li,Richard Durbin +1 more
TL;DR: Burrows-Wheeler Alignment tool (BWA) is implemented, a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps.
Journal ArticleDOI
Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles
Aravind Subramanian,Pablo Tamayo,Vamsi K. Mootha,Sayan Mukherjee,Benjamin L. Ebert,Michael A. Gillette,Amanda G. Paulovich,Scott L. Pomeroy,Todd R. Golub,Eric S. Lander,Jill P. Mesirov +10 more
TL;DR: The Gene Set Enrichment Analysis (GSEA) method as discussed by the authors focuses on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation.
Journal ArticleDOI
STAR: ultrafast universal RNA-seq aligner
Alexander Dobin,Carrie A. Davis,Felix Schlesinger,Jorg Drenkow,Chris Zaleski,Sonali Jha,Philippe Batut,Mark Chaisson,Thomas R. Gingeras +8 more
TL;DR: The Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure outperforms other aligners by a factor of >50 in mapping speed.
Journal ArticleDOI
Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma
Roger Stupp,Warren P. Mason,Martin J. van den Bent,Michael Weller,Barbara Fisher,Martin J.B. Taphoorn,Karl Belanger,Alba A. Brandes,Christine Marosi,Ulrich Bogdahn,Jürgen Curschmann,Robert C. Janzer,Samuel K. Ludwin,Thierry Gorlia,Anouk Allgeier,Denis Lacombe,J. Gregory Cairncross,Elizabeth Eisenhauer,René O. Mirimanoff +18 more
TL;DR: The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity.
Journal ArticleDOI
featureCounts: an efficient general-purpose program for assigning sequence reads to genomic features
TL;DR: FeatureCounts as discussed by the authors is a read summarization program suitable for counting reads generated from either RNA or genomic DNA sequencing experiments, which implements highly efficient chromosome hashing and feature blocking techniques.
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