Journal ArticleDOI
The future of immune checkpoint therapy
Padmanee Sharma,James P. Allison +1 more
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TLDR
The way forward for this class of novel agents lies in the ability to understand human immune responses in the tumor microenvironment, which will provide valuable information regarding the dynamic nature of the immune response and regulation of additional pathways that will need to be targeted through combination therapies to provide survival benefit for greater numbers of patients.Abstract:
Immune checkpoint therapy, which targets regulatory pathways in T cells to enhance antitumor immune responses, has led to important clinical advances and provided a new weapon against cancer. This therapy has elicited durable clinical responses and, in a fraction of patients, long-term remissions where patients exhibit no clinical signs of cancer for many years. The way forward for this class of novel agents lies in our ability to understand human immune responses in the tumor microenvironment. This will provide valuable information regarding the dynamic nature of the immune response and regulation of additional pathways that will need to be targeted through combination therapies to provide survival benefit for greater numbers of patients.read more
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Loss of PTEN Is Associated with Resistance to Anti-PD-1 Checkpoint Blockade Therapy in Metastatic Uterine Leiomyosarcoma.
Suzanne George,Diana Miao,Diana Miao,George D. Demetri,Dennis Adeegbe,Scott J. Rodig,Scott J. Rodig,Sachet A. Shukla,Mikel Lipschitz,Ali Amin-Mansour,Chandrajit P. Raut,Scott L. Carter,Scott L. Carter,Peter S. Hammerman,Peter S. Hammerman,Gordon J. Freeman,Catherine J. Wu,Catherine J. Wu,Patrick A. Ott,Kwok-Kin Wong,Eliezer M. Van Allen,Eliezer M. Van Allen +21 more
TL;DR: In this near‐complete response to PD‐1 blockade in a mesenchymal tumor, PTEN mutations and reduced expression of genes encoding neoantigens as potential mediators of resistance to immune checkpoint therapy are identified.
Journal ArticleDOI
Neoantigen landscape dynamics during human melanoma–T cell interactions
Els M. E. Verdegaal,Noel F C C de Miranda,Marten Visser,Tom J. Harryvan,Marit M. van Buuren,Marit M. van Buuren,Rikke Andersen,Rikke Andersen,Sine Reker Hadrup,Sine Reker Hadrup,Caroline E. van der Minne,Remko Schotte,Hergen Spits,John B. A. G. Haanen,John B. A. G. Haanen,Ellen Kapiteijn,Ton N. Schumacher,Sjoerd H. van der Burg +17 more
TL;DR: The dynamic interactions between cancer cells and T cells are demonstrated, which suggest that T cells mediate neoantigen immunoediting, and indicate that the therapeutic induction of broad neoantsigen-specific T-cell responses should be used to avoid tumour resistance.
Journal ArticleDOI
Pembrolizumab in Patients With Extensive-Stage Small-Cell Lung Cancer: Results From the Phase Ib KEYNOTE-028 Study
Patrick A. Ott,Elena Elez,Sandrine Hiret,Dong Wan Kim,Anne Morosky,Sanatan Saraf,Bilal Piperdi,Janice M. Mehnert +7 more
TL;DR: Pembrolizumab demonstrated promising antitumor activity in patients with pretreated, PD-L1-expressing SCLC and was consistent with the known safety profile in other tumor types.
Journal ArticleDOI
New and emerging targeted treatments in advanced non-small-cell lung cancer
TL;DR: Recent progress in the development of targeted treatments for patients with advanced non-small-cell lung cancer is reviewed, especially focusing on data from published clinical trials.
Journal ArticleDOI
Safety and Antitumor Activity of Pembrolizumab in Advanced Programmed Death Ligand 1–Positive Endometrial Cancer: Results From the KEYNOTE-028 Study
Patrick A. Ott,Yung-Jue Bang,Dominique Berton-Rigaud,Elena Elez,Michael J. Pishvaian,Hope S. Rugo,Igor Puzanov,Janice M. Mehnert,Kyaw L. Aung,Juanita Lopez,Marion Carrigan,Sanatan Saraf,Mei Chen,Jean-Charles Soria +13 more
TL;DR: Pembrolizumab demonstrated a favorable safety profile and durable antitumor activity in a subgroup of patients with heavily pretreated advanced PD-L1-positive endometrial cancer.
References
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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.
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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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The blockade of immune checkpoints in cancer immunotherapy
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Mutations of the BRAF gene in human cancer
Helen Davies,Graham R. Bignell,Charles Cox,Philip J. Stephens,Sarah Edkins,S. M. Clegg,Jon W. Teague,Hayley Woffendin,Mathew J. Garnett,William Bottomley,Neil Davis,Ed Dicks,Rebecca Ewing,Yvonne Floyd,Kristian Gray,S. Hall,Rachel Hawes,Jaime Hughes,Vivian Kosmidou,Andrew Menzies,Catherine Mould,Adrian Parker,Claire Stevens,Stephen Watt,Steven Hooper,Rebecca Wilson,Hiran Jayatilake,Barry A. Gusterson,Colin Cooper,Janet Shipley,Darren Hargrave,Kathy Pritchard-Jones,Norman J. Maitland,Georgia Chenevix-Trench,Gregory J. Riggins,Darell D. Bigner,Giuseppe Palmieri,Antonio Cossu,Adrienne M. Flanagan,Andrew G. Nicholson,Judy W. C. Ho,Suet Yi Leung,Siu Tsan Yuen,Barbara L. Weber,Hilliard F. Seigler,Timothy L. Darrow,Hugh Paterson,Richard Marais,Christopher J. Marshall,Richard Wooster,Michael R. Stratton,P. Andrew Futreal +51 more
TL;DR: BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers, with a single substitution (V599E) accounting for 80%.
Journal ArticleDOI
Signatures of mutational processes in human cancer
Ludmil B. Alexandrov,Serena Nik-Zainal,Serena Nik-Zainal,David C. Wedge,Samuel Aparicio,Sam Behjati,Sam Behjati,Andrew V. Biankin,Graham R. Bignell,Niccolo Bolli,Niccolo Bolli,Åke Borg,Anne Lise Børresen-Dale,Anne Lise Børresen-Dale,Sandrine Boyault,Birgit Burkhardt,Adam Butler,Carlos Caldas,Helen Davies,Christine Desmedt,Roland Eils,Jorunn E. Eyfjord,John A. Foekens,Mel Greaves,Fumie Hosoda,Barbara Hutter,Tomislav Ilicic,Sandrine Imbeaud,Sandrine Imbeaud,Marcin Imielinsk,Natalie Jäger,David T. W. Jones,David T. Jones,Stian Knappskog,Stian Knappskog,Marcel Kool,Sunil R. Lakhani,Carlos López-Otín,Sancha Martin,Nikhil C. Munshi,Nikhil C. Munshi,Hiromi Nakamura,Paul A. Northcott,Marina Pajic,Elli Papaemmanuil,Angelo Paradiso,John V. Pearson,Xose S. Puente,Keiran Raine,Manasa Ramakrishna,Andrea L. Richardson,Andrea L. Richardson,Julia Richter,Philip Rosenstiel,Matthias Schlesner,Ton N. Schumacher,Paul N. Span,Jon W. Teague,Yasushi Totoki,Andrew Tutt,Rafael Valdés-Mas,Marit M. van Buuren,Laura van ’t Veer,Anne Vincent-Salomon,Nicola Waddell,Lucy R. Yates,Icgc PedBrain,Jessica Zucman-Rossi,Jessica Zucman-Rossi,P. Andrew Futreal,Ultan McDermott,Peter Lichter,Matthew Meyerson,Matthew Meyerson,Sean M. Grimmond,Reiner Siebert,Elias Campo,Tatsuhiro Shibata,Stefan M. Pfister,Stefan M. Pfister,Peter J. Campbell,Peter J. Campbell,Peter J. Campbell,Michael R. Stratton,Michael R. Stratton +84 more
TL;DR: It is shown that hypermutation localized to small genomic regions, ‘kataegis’, is found in many cancer types, and this results reveal the diversity of mutational processes underlying the development of cancer.
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