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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Molecular Determinants of Response to Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing.
Hira Rizvi,Francisco Sanchez-Vega,Konnor La,Walid K. Chatila,Philip Jonsson,Darragh Halpenny,Andrew J. Plodkowski,Niamh Long,Jennifer L. Sauter,Natasha Rekhtman,Travis J. Hollmann,Kurt A. Schalper,Justin F. Gainor,Ronglai Shen,Ai Ni,Kathryn C. Arbour,Taha Merghoub,Jedd D. Wolchok,Alexandra Snyder,Jamie E. Chaft,Mark G. Kris,Charles M. Rudin,Nicholas D. Socci,Michael F. Berger,Barry S. Taylor,Ahmet Zehir,David B. Solit,Maria E. Arcila,Marc Ladanyi,Gregory J. Riely,Nikolaus Schultz,Matthew D. Hellmann +31 more
TL;DR: Targeted NGS accurately estimates tumor mutation burden and elevated TMB further improved likelihood of benefit to ICIs, and the incorporation of both TMB and PD-L1 expression into multivariable predictive models should result in greater predictive power.
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Mutant MHC class II epitopes drive therapeutic immune responses to cancer
Sebastian Kreiter,Mathias Vormehr,Niels van de Roemer,Mustafa Diken,Martin Löwer,Jan Diekmann,Sebastian Boegel,Barbara Schrörs,Fulvia Vascotto,John C. Castle,Arbel D. Tadmor,Stephen P. Schoenberger,Christoph Huber,Özlem Türeci,Ugur Sahin +14 more
TL;DR: The tailored immunotherapy approach introduced here may be regarded as a universally applicable blueprint for comprehensive exploitation of the substantial neo-epitope target repertoire of cancers, enabling the effective targeting of every patient’s tumour with vaccines produced ‘just in time’.
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TL;DR: In this Review, Drost and Clevers discuss the recent advances in organoid models of cancer and how they can be exploited to drive the translation of basic cancer research into novel patient-specific treatment regimens in the clinic.
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TL;DR: Ten key challenges facing cancer immunotherapy are defined, which range from lack of confidence in translating pre-clinical findings to identifying optimal combinations of immune-based therapies for any given patient.
Journal ArticleDOI
Primary Resistance to PD-1 Blockade Mediated by JAK1/2 Mutations.
Daniel Sanghoon Shin,Jesse M. Zaretsky,Helena Escuin-Ordinas,Angel Garcia-Diaz,Siwen Hu-Lieskovan,Anusha Kalbasi,Catherine S. Grasso,Willy Hugo,Salemiz Sandoval,Davis Y. Torrejon,Nicolaos Palaskas,Gabriel Abril Rodriguez,Giulia Parisi,Ariel M. Azhdam,Bartosz Chmielowski,Grace Cherry,Elizabeth Seja,Beata Berent-Maoz,I. Peter Shintaku,Dung Thi Le,Drew M. Pardoll,Luis A. Diaz,Paul C. Tumeh,Thomas G. Graeber,Roger S. Lo,Begoña Comin-Anduix,Antoni Ribas +26 more
TL;DR: It is proposed that JAK1/2 loss-of-function mutations are a genetic mechanism of lack of reactive PD-L1 expression and response to interferon gamma, leading to primary resistance to PD-1 blockade therapy.
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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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