Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer
Naiyer A. Rizvi,Naiyer A. Rizvi,Matthew D. Hellmann,Matthew D. Hellmann,Alexandra Snyder,Alexandra Snyder,Pia Kvistborg,Vladimir Makarov,Jonathan J. Havel,William Lee,Jianda Yuan,Phillip Wong,Teresa S. Ho,Martin L. Miller,Natasha Rekhtman,Andre L. Moreira,Fawzia Ibrahim,Cameron Bruggeman,Billel Gasmi,Roberta Zappasodi,Yuka Maeda,Chris Sander,Edward B. Garon,Taha Merghoub,Jedd D. Wolchok,Jedd D. Wolchok,Ton N. Schumacher,Timothy A. Chan,Timothy A. Chan +28 more
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TLDR
Treatment efficacy was associated with a higher number of mutations in the tumors, and a tumor-specific T cell response paralleled tumor regression in one patient, suggesting that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.Abstract:
Immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non–small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti–PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.read more
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Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors
Diana Miao,Diana Miao,Claire A. Margolis,Claire A. Margolis,Natalie I. Vokes,Natalie I. Vokes,David Liu,David Liu,Amaro Taylor-Weiner,Amaro Taylor-Weiner,Stephanie M. Wankowicz,Stephanie M. Wankowicz,Dennis Adeegbe,Daniel Keliher,Daniel Keliher,Bastian Schilling,Adam Tracy,Michael Manos,Nicole G. Chau,Glenn J. Hanna,Paz Polak,Scott J. Rodig,Scott J. Rodig,Sabina Signoretti,Sabina Signoretti,Lynette M. Sholl,Lynette M. Sholl,Jeffrey A. Engelman,Gad Getz,Pasi A. Jänne,Robert I. Haddad,Toni K. Choueiri,David A. Barbie,Rizwan Haq,Rizwan Haq,Mark M. Awad,Dirk Schadendorf,Dirk Schadendorf,F. Stephen Hodi,Joaquim Bellmunt,Kwok-Kin Wong,Kwok-Kin Wong,Peter S. Hammerman,Eliezer M. Van Allen,Eliezer M. Van Allen +44 more
TL;DR: This study uniformly analyzed whole-exome sequencing of 249 tumors and matched normal tissue from patients with clinically annotated outcomes to immune checkpoint therapy across multiple cancer types to examine additional tumor genomic features that contribute to selective response.
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β-Catenin Activation Promotes Immune Escape and Resistance to Anti–PD-1 Therapy in Hepatocellular Carcinoma
Marina Ruiz de Galarreta,Erin Bresnahan,Pedro Molina-Sánchez,Katherine E. Lindblad,Barbara Maier,Daniela Sia,Marc Puigvehí,Marc Puigvehí,Veronica Miguela,Maria Casanova-Acebes,Maxime Dhainaut,Carlos Villacorta-Martin,Aatur D. Singhi,Akshata Moghe,Johann von Felden,Johann von Felden,Lauren Tal Grinspan,Shuang Wang,Alice O. Kamphorst,Satdarshan P.S. Monga,Brian D. Brown,Augusto Villanueva,Josep M. Llovet,Josep M. Llovet,Josep M. Llovet,Miriam Merad,Amaia Lujambio +26 more
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The hallmarks of successful anticancer immunotherapy
Lorenzo Galluzzi,Lorenzo Galluzzi,Timothy A. Chan,Timothy A. Chan,Guido Kroemer,Jedd D. Wolchok,Jedd D. Wolchok,Alejandro López-Soto +7 more
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Clinical and Molecular Characteristics Associated With Survival Among Patients Treated With Checkpoint Inhibitors for Advanced Non-Small Cell Lung Carcinoma: A Systematic Review and Meta-analysis.
Chee Khoon Lee,Chee Khoon Lee,Johnathan Man,Sarah J. Lord,Wendy A Cooper,Wendy A Cooper,Matthew Links,Val Gebski,Roy S. Herbst,Richard J. Gralla,Richard J. Gralla,Tony Mok,James Chih-Hsin Yang +12 more
TL;DR: Checkpoint inhibitors, compared with docetaxel, are associated with significantly prolong overall survival in second-line therapy in NSCLC and should be considered only after other effective therapies have been exhausted.
Journal ArticleDOI
Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma
David A. Braun,David A. Braun,Yue Hou,Ziad Bakouny,Miriam Ficial,Miriam Ficial,Miriam Sant’ Angelo,Miriam Sant’ Angelo,Juliet Forman,Juliet Forman,Petra Ross-Macdonald,Ashton C. Berger,Opeyemi Jegede,Liudmilla Elagina,John A. Steinharter,Maxine Sun,Megan Wind-Rotolo,Jean-Christophe Pignon,Jean-Christophe Pignon,Andrew D. Cherniack,Andrew D. Cherniack,Lee Lichtenstein,Donna Neuberg,Paul J. Catalano,Gordon J. Freeman,Arlene H. Sharpe,David F. McDermott,David F. McDermott,Eliezer M. Van Allen,Eliezer M. Van Allen,Sabina Signoretti,Sabina Signoretti,Catherine J. Wu,Catherine J. Wu,Sachet A. Shukla,Sachet A. Shukla,Toni K. Choueiri +36 more
TL;DR: A pooled genetic, transcriptomic and immunopathologic analysis of over 500 tumors from patients with advanced renal cell cancer suggests that response to PD-1 blockade depends on both CD8 + T cell infiltration and enrichment of tumor-intrinsic somatic alterations.
References
More filters
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
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma.
F. Stephen Hodi,Steven J. O'Day,David F. McDermott,R. W. Weber,Jeffrey A. Sosman,John B. A. G. Haanen,Rene Gonzalez,Caroline Robert,Dirk Schadendorf,Jessica C. Hassel,Wallace Akerley,Alfons J.M. van den Eertwegh,Jose Lutzky,Paul Lorigan,Julia Vaubel,Gerald P. Linette,David W. Hogg,Christian H. Ottensmeier,Céleste Lebbé,Christian Peschel,Ian Quirt,Joseph I. Clark,Jedd D. Wolchok,Jeffrey S. Weber,Jason Tian,Michael Yellin,Geoffrey M. Nichol,Axel Hoos,Walter J. Urba +28 more
TL;DR: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma.
Journal ArticleDOI
A method and server for predicting damaging missense mutations.
Ivan Adzhubei,Steffen Schmidt,Leonid Peshkin,Vasily Ramensky,Anna Gerasimova,Peer Bork,Alexey S. Kondrashov,Shamil R. Sunyaev +7 more
TL;DR: A new method and the corresponding software tool, PolyPhen-2, which is different from the early tool polyPhen1 in the set of predictive features, alignment pipeline, and the method of classification is presented and performance, as presented by its receiver operating characteristic curves, was consistently superior.
Journal ArticleDOI
Integrative genomics viewer
James T. Robinson,Helga Thorvaldsdottir,Wendy Winckler,Mitchell Guttman,Eric S. Lander,Eric S. Lander,Gad Getz,Jill P. Mesirov +7 more
TL;DR: In this article, the authors present an approach for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data.
Journal ArticleDOI
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.
Suzanne L. Topalian,F. Stephen Hodi,Julie R. Brahmer,Scott N. Gettinger,David Smith,David F. McDermott,John D. Powderly,Richard D. Carvajal,Jeffrey A. Sosman,Michael B. Atkins,Philip D. Leming,David R. Spigel,Scott J. Antonia,Leora Horn,Charles G. Drake,Drew M. Pardoll,Lieping Chen,William H. Sharfman,Robert A. Anders,Janis M. Taube,Tracee L. McMiller,Haiying Xu,Alan J. Korman,Maria Jure-Kunkel,Shruti Agrawal,Dan McDonald,Georgia Kollia,Ashok Kumar Gupta,Jon M. Wigginton,Mario Sznol +29 more
TL;DR: Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use.
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