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
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
Citations
More filters
Journal ArticleDOI
Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden
Zachary R. Chalmers,Caitlin F. Connelly,David Fabrizio,Siraj M. Ali,Riley Ennis,Alexa B. Schrock,Brittany Campbell,Adam Shlien,Juliann Chmielecki,Franklin W. Huang,Yuting He,James Sun,Uri Tabori,Mark Kennedy,Daniel S. Lieber,Steven Roels,Jared White,G. Otto,Jeffrey S. Ross,Levi A. Garraway,Levi A. Garraway,Vincent A. Miller,Phillip J. Stephens,Garrett M. Frampton +23 more
TL;DR: Measurements of TMB from comprehensive genomic profiling are strongly reflective of measurements from whole exome sequencing and model that below 0.5 Mb the variance in measurement increases significantly, demonstrating that many disease types have a substantial portion of patients with high TMB who might benefit from immunotherapy.
Journal ArticleDOI
Genomic and transcriptomic features of response to anti-pd-1 therapy in metastatic melanoma
Willy Hugo,Jesse M. Zaretsky,Lu Sun,Chunying Song,Blanca Homet Moreno,Siwen Hu-Lieskovan,Beata Berent-Maoz,Jia Pang,Bartosz Chmielowski,Grace Cherry,Elizabeth Seja,Shirley H. Lomeli,Xiangju Kong,Mark C. Kelley,Jeffrey A. Sosman,Douglas B. Johnson,Antoni Ribas,Roger S. Lo +17 more
TL;DR: It is found that overall high mutational loads associate with improved survival, and tumors from responding patients are enriched for mutations in the DNA repair gene BRCA2, suggesting that attenuating the biological processes that underlie IPRES may improve anti-PD-1 response in melanoma and other cancer types.
Journal ArticleDOI
Pan-cancer Immunogenomic Analyses Reveal Genotype-Immunophenotype Relationships and Predictors of Response to Checkpoint Blockade
Pornpimol Charoentong,Francesca Finotello,Mihaela Angelova,Clemens Mayer,Mirjana Efremova,Dietmar Rieder,Hubert Hackl,Zlatko Trajanoski +7 more
TL;DR: The immunophenoscore was a superior predictor of response to anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) and anti-programmed cell death protein 1 (anti-PD-1) antibodies in two independent validation cohorts and may help inform cancer immunotherapy and facilitate the development of precision immuno-oncology.
Journal ArticleDOI
Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade
Nicholas McGranahan,Nicholas McGranahan,Andrew Furness,Rachel Rosenthal,Sofie Ramskov,Rikke Birgitte Lyngaa,Sunil Kumar Saini,Mariam Jamal-Hanjani,Gareth A. Wilson,Nicolai Juul Birkbak,Crispin T. Hiley,Thomas B.K. Watkins,Seema Shafi,Nirupa Murugaesu,Richard Mitter,Ayse U. Akarca,Joseph Linares,Teresa Marafioti,Jake Y. Henry,Eliezer M. Van Allen,Eliezer M. Van Allen,Diana Miao,Diana Miao,Bastian Schilling,Dirk Schadendorf,Levi A. Garraway,Levi A. Garraway,Vladimir Makarov,Naiyer A. Rizvi,Alexandra Snyder,Alexandra Snyder,Matthew D. Hellmann,Matthew D. Hellmann,Taha Merghoub,Jedd D. Wolchok,Jedd D. Wolchok,Sachet A. Shukla,Sachet A. Shukla,Catherine J. Wu,Karl S. Peggs,Timothy A. Chan,Sine Reker Hadrup,Sergio A. Quezada,Charles Swanton +43 more
TL;DR: A relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas and the impact of neoantigens intratumor heterogeneity (ITH) on antitumor immunity is demonstrated.
Journal ArticleDOI
Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden
Matthew D. Hellmann,Tudor-Eliade Ciuleanu,Adam Pluzanski,Jong-Seok Lee,Gregory A. Otterson,Clarisse Audigier-Valette,Elisa Minenza,Helena Linardou,Sjaak Burgers,Pamela Salman,Hossein Borghaei,Suresh S. Ramalingam,Julie R. Brahmer,Martin Reck,Kenneth J. O'Byrne,William J. Geese,George Green,Han Chang,Joseph D. Szustakowski,Prabhu Bhagavatheeswaran,Diane Healey,Yali Fu,F. E. Nathan,Luis Paz-Ares +23 more
TL;DR: The benefit of nivolumab plus ipilimumab over chemotherapy was broadly consistent within subgroups, including patients with a PD‐L1 expression level of at least 1% and those with a level of less than 1%.
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.
Related Papers (5)
PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
Dung T. Le,Jennifer N. Uram,Hao Wang,Bjarne Bartlett,Holly Kemberling,Aleksandra Eyring,Andrew D. Skora,Brandon Luber,Nilofer S. Azad,Daniel A. Laheru,Barbara A. Biedrzycki,Ross C. Donehower,Atif Zaheer,George A. Fisher,Todd S. Crocenzi,James J. Lee,Steven M. Duffy,Richard M. Goldberg,Richard M. Goldberg,Albert de la Chapelle,Albert de la Chapelle,Minori Koshiji,Feriyl Bhaijee,Thomas Huebner,Ralph H. Hruban,Laura D. Wood,Nathan Cuka,Drew M. Pardoll,Nickolas Papadopoulos,Kenneth W. Kinzler,Shibin Zhou,Toby C. Cornish,Janis M. Taube,Robert A. Anders,James R. Eshleman,Bert Vogelstein,Luis A. Diaz +36 more
Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer
Hossein Borghaei,Luis Paz-Ares,Leora Horn,D. R. Spigel,M. Steins,Neal Ready,L.Q. Chow,Everett E. Vokes,Enriqueta Felip,Esther Holgado,F. Barlesi,M. Kohlhufl,Oscar Arrieta,Marco Angelo Burgio,J. Fayette,H. Lena,Elena Poddubskaya,David E. Gerber,Scott N. Gettinger,Charles M. Rudin,Naiyer A. Rizvi,L. Crina,G. R. Blumenschein,Scott J. Antonia,C. Dorange,C. T. Harbison,F. Graf Finckenstein,Julie R. Brahmer +27 more
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
Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer
Julie R. Brahmer,Karen L. Reckamp,Paul Baas,Lucio Crinò,Wilfried Eberhardt,Elena Poddubskaya,Scott J. Antonia,Adam Pluzanski,Everett E. Vokes,Esther Holgado,David M. Waterhouse,Neal Ready,Justin F. Gainor,Osvaldo Arén Frontera,Libor Havel,Martin Steins,Marina Chiara Garassino,Joachim G.J.V. Aerts,Manuel Domine,Luis Paz-Ares,Martin Reck,Christine Baudelet,Christopher T. Harbison,Brian Lestini,David R. Spigel +24 more