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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The Molecular Landscape of Recurrent and Metastatic Head and Neck Cancers: Insights From a Precision Oncology Sequencing Platform.
Luc G. T. Morris,Raghu Chandramohan,Lyndsay West,Ahmet Zehir,Debyani Chakravarty,David G. Pfister,Richard J. Wong,Nancy Y. Lee,Eric J. Sherman,Shrujal S. Baxi,Ian Ganly,Bhuvanesh Singh,Jatin P. Shah,Ashok R. Shaha,Jay O. Boyle,Snehal G. Patel,Benjamin R. Roman,Christopher A. Barker,Sean McBride,Timothy A. Chan,Snjezana Dogan,David M. Hyman,Michael F. Berger,David B. Solit,Nadeem Riaz,Alan L. Ho +25 more
TL;DR: The genetic profiles of recurrent and metastatic tumors were often distinct from primary tumors, and the molecular landscape of advanced disease and rare cancer subtypes, both predominant challenges in head and neck oncology.
Journal ArticleDOI
Pembrolizumab as first-line therapy for patients with PD-L1-positive advanced non-small cell lung cancer: a phase 1 trial.
Rina Hui,Edward B. Garon,Jonathan W. Goldman,Natasha B. Leighl,Matthew D. Hellmann,Amita Patnaik,Leena Gandhi,Joseph Paul Eder,Myung-Ju Ahn,Leora Horn,Enriqueta Felip,Enric Carcereny,Reshma A. Rangwala,Gregory M. Lubiniecki,Jin Zhang,Kenneth Emancipator,Charlotte Roach,Naiyer A. Rizvi +17 more
TL;DR: Pembrolizumab provides promising long-term OS benefit with a manageable safety profile for PD-L1-expressing treatment-naive advanced NSCLC, with greatest efficacy observed in patients with TPS ≥50%.
Journal ArticleDOI
Suppression of Type I IFN Signaling in Tumors Mediates Resistance to Anti-PD-1 Treatment That Can Be Overcome by Radiotherapy.
Xiaohong Wang,Jonathan E. Schoenhals,Ailin Li,David Valdecanas,Huiping Ye,Fenglin Zang,Chad Tang,Ming Tang,Chang Gong Liu,Xiuping Liu,Sunil Krishnan,James P. Allison,Padmanee Sharma,Patrick Hwu,Ritsuko Komaki,Willem W. Overwijk,Daniel R. Gomez,Joe Y. Chang,Stephen M. Hahn,Maria Angelica Cortez,James W. Welsh +20 more
TL;DR: Localized radiotherapy induced IFNβ production, thereby elevating MHC class I expression on both parental and resistant tumor cells and restoring the responsiveness of resistant tumors to anti-PD-1 therapy, and adjuvant radiotherapy can overcome resistance.
Journal ArticleDOI
Noninvasive Early Identification of Therapeutic Benefit from Immune Checkpoint Inhibition.
Barzin Y. Nabet,Mohammad Shahrokh Esfahani,Everett J. Moding,Emily G. Hamilton,Jacob J. Chabon,Hira Rizvi,Chloé B. Steen,Aadel A. Chaudhuri,Chih Long Liu,Angela B. Hui,Diego Almanza,Henning Stehr,Linda Gojenola,Rene F. Bonilla,Michael C. Jin,Young-Jun Jeon,Young-Jun Jeon,Diane Tseng,Cailian Liu,Taha Merghoub,Joel W. Neal,Heather A. Wakelee,Sukhmani K. Padda,Kavitha Ramchandran,Millie Das,Millie Das,Andrew J. Plodkowski,Christopher H. Yoo,Emily Chen,Ryan B. Ko,Aaron M. Newman,Matthew D. Hellmann,Ash A. Alizadeh,Maximilian Diehn +33 more
TL;DR: It is demonstrated that pre-treatment circulating tumor DNA (ctDNA) and peripheral CD8 T cell levels are independently associated with DCB and that ctDNA dynamics after a single infusion can aid in identification of patients who will achieve durable clinical benefit (DCB).
Journal ArticleDOI
Cancer Neoantigens and Applications for Immunotherapy
TL;DR: These neoantigens could be useful both as predictors of immune checkpoint blockade therapy response and/or incorporated in therapeutic vaccination strategies for personalized vaccines against nonself peptides.
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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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