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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Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors
Bertrand Routy,Bertrand Routy,Bertrand Routy,Lisa Derosa,Lisa Derosa,Lisa Derosa,Connie P.M. Duong,Connie P.M. Duong,Maryam Tidjani Alou,Maryam Tidjani Alou,Maryam Tidjani Alou,Romain Daillère,Romain Daillère,Romain Daillère,Aurélie Fluckiger,Aurélie Fluckiger,Meriem Messaoudene,Meriem Messaoudene,Conrad Rauber,Conrad Rauber,Conrad Rauber,Maria Paula Roberti,Maria Paula Roberti,Marine Fidelle,Marine Fidelle,Caroline Flament,Caroline Flament,Vichnou Poirier-Colame,Vichnou Poirier-Colame,Paule Opolon,Christophe Klein,Kristina Iribarren,Laura Mondragón,Nicolas Jacquelot,Nicolas Jacquelot,Nicolas Jacquelot,Bo Qu,Bo Qu,Bo Qu,Gladys Ferrere,Gladys Ferrere,Gladys Ferrere,Céline Clémenson,Céline Clémenson,Laura Mezquita,Jordi Remon Masip,C. Naltet,Solenn Brosseau,Coureche Kaderbhai,Corentin Richard,Hira Rizvi,Florence Levenez,Nathalie Galleron,Benoit Quinquis,Nicolas Pons,Bernhard Ryffel,Veronique Minard-Colin,Patrick Gonin,Jean-Charles Soria,Eric Deutsch,Eric Deutsch,Yohann Loriot,Yohann Loriot,François Ghiringhelli,Gérard Zalcman,François Goldwasser,B. Escudier,B. Escudier,Matthew D. Hellmann,Matthew D. Hellmann,Alexander M.M. Eggermont,Alexander M.M. Eggermont,Didier Raoult,Laurence Albiges,Laurence Albiges,Guido Kroemer,Laurence Zitvogel +76 more
TL;DR: It is found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition, and Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer.
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Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy.
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