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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Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma
David F. McDermott,Mahrukh Huseni,Michael B. Atkins,Robert J. Motzer,Brian I. Rini,Bernard Escudier,Lawrence Fong,Richard W. Joseph,Sumanta K. Pal,James A. Reeves,Mario Sznol,John D. Hainsworth,W. Kimryn Rathmell,Walter M. Stadler,Thomas E. Hutson,Martin Gore,Alain Ravaud,Sergio Bracarda,Cristina Suarez,Riccardo Danielli,Viktor Gruenwald,Toni K. Choueiri,Dorothee Nickles,Suchit Jhunjhunwala,Elisabeth Piault-Louis,Alpa Thobhani,Jiaheng Qiu,Daniel S. Chen,Priti S. Hegde,Christina Schiff,Gregg Fine,Thomas Powles +31 more
TL;DR: Molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade.
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Immunotherapy in colorectal cancer: rationale, challenges and potential.
Karuna Ganesh,Zsofia K. Stadler,Andrea Cercek,Robin B. Mendelsohn,Jinru Shia,Neil H. Segal,Luis A. Diaz +6 more
TL;DR: Clinical development of immune checkpoint inhibition in CRC leading to regulatory approvals for the treatment of dMMR–MSI-H CRC is reviewed and new advances in expanding the efficacy of immunotherapy to early-stage CRC and CRC that is mismatch-repair-proficient and has low microsatellite instability (pMMR- MSI-L) are focused on.
Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq
Itay Tirosh,Benjamin Izar,Daniel J. Treacy,John J. Trombetta,Asaf Rotem,Christopher Rodman,Christine G. Lian,George F. Murphy,Mohammad Fallahi-Sichani,Ken Dutton-Regester,Jia-Ren Lin,Ofir Cohen,Parin Shah,Diana Lu,Alexandra-Chloé Villani,Aleksandr Andreev,E.M. Van Allen,Monica M. Bertagnolli,Peter K. Sorger,Ryan J. Sullivan,Keith T. Flaherty,Dennie T. Frederick,Judit Jané-Valbuena,Orit Rozenblatt-Rosen,Sanjay M. Prakadan,Marc H. Wadsworth,Alex S. Genshaft,Travis K. Hughes,Carly G. K. Ziegler,Samuel W. Kazer,Alethe Gaillard de Saint Germain,Kellie E. Kolb,Cory M. Johannessen,Clifford H. Yoon,Alex K. Shalek,Aviv Regev,Levi A. Garraway +36 more
TL;DR: Tirosh et al. as discussed by the authors applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, and endothelial cells.
Journal ArticleDOI
Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma
Diana Miao,Diana Miao,Claire A. Margolis,Claire A. Margolis,Wenhua Gao,Martin H. Voss,Martin H. Voss,Wei Li,Dylan J. Martini,Craig Norton,Dominick Bossé,Stephanie M. Wankowicz,Stephanie M. Wankowicz,Dana Cullen,Christine Horak,Megan Wind-Rotolo,Adam Tracy,Marios Giannakis,Marios Giannakis,F.S. Hodi,Charles G. Drake,Mark W. Ball,Mohamad E. Allaf,Alexandra Snyder,Matthew D. Hellmann,Matthew D. Hellmann,Thai H. Ho,Robert J. Motzer,Robert J. Motzer,Sabina Signoretti,William G. Kaelin,William G. Kaelin,Toni K. Choueiri,Eliezer M. Van Allen,Eliezer M. Van Allen +34 more
TL;DR: Clinical benefit was associated with loss-of-function mutations in the PBRM1 gene, which encodes a subunit of the PBAF switch-sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, and may alter global tumor-cell expression profiles to influence responsiveness to immune checkpoint therapy.
Journal ArticleDOI
Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab
David R. Gandara,Sarah M. Paul,Marcin Kowanetz,Erica B. Schleifman,Wei Zou,Yan Li,Achim Rittmeyer,Louis Fehrenbacher,Geoff Otto,Christine Malboeuf,Daniel S. Lieber,Doron Lipson,Jacob Silterra,Lukas C. Amler,Todd Riehl,Craig Cummings,Priti S. Hegde,Alan Sandler,Marcus Ballinger,David Fabrizio,Tony Mok,David S. Shames +21 more
TL;DR: It is shown that high bTMB is a clinically actionable biomarker for atezolizumab in NSCLC, and a blood-based DNA sequencing assay to infer tumor mutational burden in the absence of tumor biopsy predicts response to PD-L1 blockade in patients with non-small-cell lung cancer.
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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