Journal ArticleDOI
Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency
Eric Bouffet,Valérie Larouche,Brittany Campbell,Daniele Merico,Richard de Borja,Melyssa Aronson,Carol Durno,Joerg Krueger,Vanja Cabric,Vijay Ramaswamy,Nataliya Zhukova,Gary Mason,Roula Farah,Samina Afzal,Michal Yalon,Gideon Rechavi,Vanan Magimairajan,Michael Walsh,Shlomi Constantini,Rina Dvir,Ronit Elhasid,Alyssa Reddy,Michael Osborn,Michael J. Sullivan,Jordan R. Hansford,Andrew Dodgshun,Nancy Klauber-DeMore,Lindsay L. Peterson,Sunil J. Patel,Scott Lindhorst,Jeffrey Atkinson,Zane Cohen,Rachel Laframboise,Peter B. Dirks,Michael D. Taylor,David Malkin,Steffen Albrecht,Roy W. R. Dudley,Nada Jabado,Cynthia Hawkins,Adam Shlien,Uri Tabori +41 more
TLDR
This report of initial and durable responses of recurrent GBM to immune checkpoint inhibition may have implications for GBM in general and other hypermutant cancers arising from primary (genetic predisposition) or secondary MMRD.Abstract:
PurposeRecurrent glioblastoma multiforme (GBM) is incurable with current therapies. Biallelic mismatch repair deficiency (bMMRD) is a highly penetrant childhood cancer syndrome often resulting in GBM characterized by a high mutational burden. Evidence suggests that high mutation and neoantigen loads are associated with response to immune checkpoint inhibition.Patients and MethodsWe performed exome sequencing and neoantigen prediction on 37 bMMRD cancers and compared them with childhood and adult brain neoplasms. Neoantigen prediction bMMRD GBM was compared with responsive adult cancers from multiple tissues. Two siblings with recurrent multifocal bMMRD GBM were treated with the immune checkpoint inhibitor nivolumab.ResultsAll malignant tumors (n = 32) were hypermutant. Although bMMRD brain tumors had the highest mutational load because of secondary polymerase mutations (mean, 17,740 ± standard deviation, 7,703), all other high-grade tumors were hypermutant (mean, 1,589 ± standard deviation, 1,043), simila...read more
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Tumor mutational load predicts survival after immunotherapy across multiple cancer types.
Robert M. Samstein,Chung-Han Lee,Chung-Han Lee,Alexander N. Shoushtari,Alexander N. Shoushtari,Matthew D. Hellmann,Matthew D. Hellmann,Ronglai Shen,Yelena Y. Janjigian,Yelena Y. Janjigian,David Barron,Ahmet Zehir,Emmet Jordan,Antonio Omuro,Thomas Kaley,Sviatoslav M. Kendall,Robert J. Motzer,Robert J. Motzer,A. Ari Hakimi,Martin H. Voss,Martin H. Voss,Paul Russo,Jonathan E. Rosenberg,Jonathan E. Rosenberg,Gopa Iyer,Gopa Iyer,Bernard H. Bochner,Dean F. Bajorin,Dean F. Bajorin,Hikmat Al-Ahmadie,Jamie E. Chaft,Jamie E. Chaft,Charles M. Rudin,Charles M. Rudin,Gregory J. Riely,Gregory J. Riely,Shrujal S. Baxi,Shrujal S. Baxi,Alan L. Ho,Alan L. Ho,Richard J. Wong,David G. Pfister,David G. Pfister,Jedd D. Wolchok,Jedd D. Wolchok,Christopher A. Barker,Philip H. Gutin,Cameron Brennan,Viviane Tabar,Ingo K. Mellinghoff,Lisa M. DeAngelis,Charlotte E. Ariyan,Nancy Y. Lee,William D. Tap,William D. Tap,Mrinal M. Gounder,Mrinal M. Gounder,Sandra P. D'Angelo,Sandra P. D'Angelo,Leonard B. Saltz,Leonard B. Saltz,Zsofia K. Stadler,Zsofia K. Stadler,Howard I. Scher,Howard I. Scher,José Baselga,José Baselga,Pedram Razavi,Pedram Razavi,Christopher A. Klebanoff,Christopher A. Klebanoff,Rona Yaeger,Rona Yaeger,Neil H. Segal,Neil H. Segal,Geoffrey Y. Ku,Geoffrey Y. Ku,Ronald P. DeMatteo,Marc Ladanyi,Naiyer A. Rizvi,Michael F. Berger,Nadeem Riaz,David B. Solit,Timothy A. Chan,Luc G. T. Morris +84 more
TL;DR: Analysis of advanced cancer patients treated with immune-checkpoint inhibitors shows that tumor mutational burden, as assessed by targeted next-generation sequencing, predicts survival after immunotherapy across multiple cancer types.
Journal ArticleDOI
Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment.
Qianghu Wang,Baoli Hu,Xin Hu,Xin Hu,Hoon Kim,Massimo Squatrito,Lisa Scarpace,Ana C. deCarvalho,Sali Lyu,Pengping Li,Yan Li,Floris P. Barthel,Hee Jin Cho,Hee Jin Cho,Yu Hsi Lin,Nikunj Satani,Emmanuel Martinez-Ledesma,Siyuan Zheng,Edward I. Chang,Charles Etienne Gabriel Sauvé,Adriana Olar,Zheng D. Lan,Gaetano Finocchiaro,Joanna J. Phillips,Mitchel S. Berger,Konrad Gabrusiewicz,Guocan Wang,Eskil Eskilsson,Jian Hu,Tom Mikkelsen,Ronald A. DePinho,Florian L. Muller,Amy B. Heimberger,Erik P. Sulman,Do Hyun Nam,Do Hyun Nam,Roel G.W. Verhaak +36 more
TL;DR: Gene signature-based tumor microenvironment inference revealed a decrease in invading monocytes and a subtype-dependent increase in macrophages/microglia cells upon disease recurrence within weeks of diagnosis and at recurrence.
Journal ArticleDOI
The Microenvironmental Landscape of Brain Tumors
TL;DR: A number of distinct features of the brain tumor microenvironment are discussed, including brain-resident cell types, the blood-brain barrier, and various aspects of the immune-suppressive environment.
Journal ArticleDOI
The landscape of genomic alterations across childhood cancers
Susanne Gröbner,Barbara C. Worst,Joachim Weischenfeldt,Joachim Weischenfeldt,Ivo Buchhalter,Kortine Kleinheinz,Vasilisa A. Rudneva,Pascal Johann,Gnana Prakash Balasubramanian,Maia Segura-Wang,Sebastian Brabetz,Sebastian Bender,Barbara Hutter,Dominik Sturm,Elke Pfaff,Daniel Hübschmann,Gideon Zipprich,Michael Heinold,Michael Heinold,Jürgen Eils,Christian Lawerenz,Serap Erkek,Sander Lambo,Sebastian M. Waszak,Claudia Blattmann,Arndt Borkhardt,Arndt Borkhardt,Michaela Kuhlen,Michaela Kuhlen,Angelika Eggert,Angelika Eggert,Simone Fulda,Manfred Gessler,Jenny Wegert,Roland Kappler,Roland Kappler,Daniel Baumhoer,Stefan Burdach,Stefan Burdach,Renate Kirschner-Schwabe,Renate Kirschner-Schwabe,Udo Kontny,Andreas E. Kulozik,Andreas E. Kulozik,Dietmar R. Lohmann,Simone Hettmer,Cornelia Eckert,Cornelia Eckert,Stefan S. Bielack,Michaela Nathrath,Michaela Nathrath,Charlotte M. Niemeyer,Charlotte M. Niemeyer,Gunther Richter,Gunther Richter,Johannes H. Schulte,Johannes H. Schulte,Reiner Siebert,Frank Westermann,Jan J. Molenaar,Gilles Vassal,Hendrik Witt,Peter Lichter,Ursula Weber,Roland Eils,Roland Eils,Andrey Korshunov,Olaf Witt,Stefan Pfister,Guido Reifenberger,J Felsberg,Christof von Kalle,Manfred Schmidt,Cynthia Bartholomä,Michael Taylor,David T. W. Jones,Natalie Jäger,Korbel Jo,Adrian M. Stütz,Tobias Rausch,Bernhard Radlwimmer,Marie-Laure Yaspo,Hans Lehrach,Hans-Jörg Warnatz,Pablo Landgraf,Benedikt Brors,Marc Zapatka,Marc Zapatka,Susanne Wagner,Susanne Wagner,Andrea Haake,Julia Richter,Gesine Richter,Gesine Richter,Chris Lawerenz,Jules Kerssemakers,Christina Jaeger-Schmidt,Ingrid Scholz,Anke K. Bergmann,Christoph Borst,Birgit Burkhardt,Alexander Claviez,Martin Dreyling,Martin Dreyling,Sonja Eberth,Hermann Einsele,Norbert Frickhofen,Siegfried Haas,Martin-Leo Hansmann,Dennis Karsch,Michael Kneba,Jasmin Lisfeld,Luisa Mantovani-Löffler,Marius Rohde,German Ott,Christina Stadler,Peter Staib,Stephan Stilgenbauer,Lorenz Trümper,Thorsten Zenz,Dieter Kube,Ralf Küppers,Marc A. Weniger,Michael Hummel,Wolfram Klapper,Ulrike Kostezka,Dido Lenze,Peter Möller,Andreas Rosenwald,Monika Szczepanowski,Ole Ammerpohl,Sietse M. Aukema,Vera Binder,Jessica I. Hoell,Ellen Leich,Cristina López,Inga Nagel,Jordan Pischimariov,Philip Rosenstiel,Markus Schilhabel,Stefan Schreiber,Inga Vater,Rabea Wagener,Stephan H. Bernhart,Hans Binder,Gero Doose,Steve Hoffmann,Lydia Hopp,Helene Kretzmer,Markus Kreuz,David Langenberger,Markus Loeffler,Maciej Rosolowski,Matthias Schlesner,Peter F. Stadler,Stephanie Sungalee,Christian P. Kratz,Cornelis M. van Tilburg,Christof M. Kramm,Gudrun Fleischhack,Gudrun Fleischhack,Uta Dirksen,Stefan Rutkowski,Michael C. Frühwald,Katja von Hoff,Stephan Wolf,Thomas Klingebiel,Thomas Klingebiel,Ewa Koscielniak,Jan Koster,Adam C. Resnick,Jinghui Zhang,Yanling Liu,Xin Zhou,Angela J. Waanders,Danny A. Zwijnenburg,Pichai Raman,Ursula D. Weber,Paul A. Northcott,Kristian W. Pajtler,Marcel Kool,Rosario M. Piro,Jan O. Korbel,David T.W. Jones,Lukas Chavez,Stefan M. Pfister +185 more
TL;DR: The data suggest that 7–8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.
Journal ArticleDOI
Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.
Timothy F. Cloughesy,Aaron Mochizuki,Joey Orpilla,Willy Hugo,Alexander Lee,Tom B. Davidson,Anthony C. Wang,Benjamin M. Ellingson,Julie A. Rytlewski,Catherine Sanders,Eric S. Kawaguchi,Lin Du,Gang Li,William H. Yong,Sarah C. Gaffey,Adam L. Cohen,Ingo K. Mellinghoff,Eudocia Q. Lee,David A. Reardon,Barbara O’Brien,Nicholas Butowski,Phioanh L. Nghiemphu,Jennifer Clarke,Isabel Arrillaga-Romany,Howard Colman,Thomas Kaley,John de Groot,Linda M. Liau,Patrick Y. Wen,Robert M. Prins +29 more
TL;DR: It is suggested that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.
References
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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
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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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Edward B. Garon,Naiyer A. Rizvi,Rina Hui,Natasha B. Leighl,Ani Sarkis Balmanoukian,Joseph Paul Eder,Amita Patnaik,Charu Aggarwal,Matthew A. Gubens,Leora Horn,Enric Carcereny,Myung-Ju Ahn,Enriqueta Felip,Jong-Seok Lee,Matthew D. Hellmann,Omid Hamid,Jonathan W. Goldman,Jean-Charles Soria,Marisa Dolled-Filhart,Ruth Z. Rutledge,Jin Zhang,Jared Lunceford,Reshma A. Rangwala,Gregory M. Lubiniecki,Charlotte Roach,Kenneth Emancipator,Leena Gandhi +26 more
TL;DR: Pembrolizumab had an acceptable side-effect profile and showed antitumor activity in patients with advanced non-small-cell lung cancer and PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy of pembrolIZumab.
Journal ArticleDOI
Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma
Alexandra Snyder,Vladimir Makarov,Taha Merghoub,Jianda Yuan,Jesse M. Zaretsky,Alexis Desrichard,Logan A. Walsh,Michael A. Postow,Phillip Wong,Teresa S. Ho,Travis J. Hollmann,Cameron Bruggeman,Kasthuri Kannan,Yanyun Li,Ceyhan Elipenahli,Cailian Liu,Christopher T. Harbison,Lisu Wang,Antoni Ribas,Jedd D. Wolchok,Jedd D. Wolchok,Timothy A. Chan +21 more
TL;DR: In this paper, the authors provide clarification and correction to their article "Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma" (Dec. 4, 2014, issue).
Journal ArticleDOI
Nivolumab and ipilimumab versus ipilimumab in untreated melanoma
Michael A. Postow,Jason Chesney,Anna C. Pavlick,Caroline Robert,Kenneth F. Grossmann,David F. McDermott,Gerald P. Linette,Nicolas Meyer,Jeffrey K. Giguere,Sanjiv S. Agarwala,Montaser Shaheen,Marc S. Ernstoff,David R. Minor,April K.S. Salama,Matthew H. Taylor,Patrick A. Ott,Linda Rollin,Christine Horak,Paul Gagnier,Jedd D. Wolchok,F. Stephen Hodi +20 more
TL;DR: The objective-response rate and the progression-free survival among patients with advanced melanoma who had not previously received treatment were significantly greater with nivolumab combined with ipilimumab than with ipILimumab monotherapy.
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