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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Tumor-immune profiling of murine syngeneic tumor models as a framework to guide mechanistic studies and predict therapy response in distinct tumor microenvironments.
Jun Yu,Sabyasachi Bhattacharya,Niranjan Yanamandra,David J. Kilian,Hong Shi,Sapna Yadavilli,Yuliya V. Katlinskaya,Heather Kaczynski,Michael Conner,William G. Benson,Ashleigh Hahn,Laura M. Seestaller-Wehr,Meixia Bi,Nicholas J. Vitali,Lyuben Tsvetkov,Wendy S. Halsey,Ashley M. Hughes,Christopher M. Traini,Hui Zhou,Junping Jing,Tae Lee,David J. Figueroa,Sara Brett,Christopher B. Hopson,James F. Smothers,Axel Hoos,Roopa Srinivasan +26 more
TL;DR: The tumor microenvironment of four commonly used mouse syngeneic tumor models is characterized and it is proposed each model possesses a unique tumor-immune infiltrate profile that can be probed with immunotherapies to inform on anti-tumor mechanisms and treatment strategies in human tumors with similar profiles.
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Molecular approaches for classifying endometrial carcinoma.
Josep M. Piulats,Esther Guerra,M. Gil-Martin,Berta Roman-Canal,Sonia Gatius,Rebeca Sanz-Pamplona,Ana Velasco,August Vidal,Xavier Matias-Guiu +8 more
TL;DR: Combining pathologic classification and the surrogate TCGA molecular classification for high-grade endometrial carcinomas, as an option to improve assessment of prognosis, is suggested.
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Translating cancer genomes and transcriptomes for precision oncology
TL;DR: Key applications and new directions are outlined for translating the cancer genome and transcriptome into patient care in the clinic in a review of next‐generation DNA sequencing technologies.
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Biochemical Aspects of PD-L1 Regulation in Cancer Immunotherapy.
TL;DR: This review focuses on summarizing PD-L1 regulation and its potential roles in regulating antitumor immune response, with purpose to optimize anti-PD-1/PD- L1 therapies, benefiting a wider cancer patient population.
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A dormant TIL phenotype defines non-small cell lung carcinomas sensitive to immune checkpoint blockers
Scott N. Gettinger,June-Seek Choi,Nikita Mani,Nikita Mani,Miguel F. Sanmamed,Ila Datar,Ila Datar,Ryan T. Sowell,Victor Y. Du,Edward Kaftan,Sarah B. Goldberg,Weilai Dong,Daniel Zelterman,Katerina Politi,Katerina Politi,Paula B. Kavathas,Susan M. Kaech,Xiaoqing Yu,Hongyu Zhao,Joseph Schlessinger,Richard P. Lifton,David L. Rimm,David L. Rimm,Lieping Chen,Roy S. Herbst,Kurt A. Schalper,Kurt A. Schalper +26 more
TL;DR: It is demonstrated that dormant TILs can be reinvigorated upon PD-1 blockade in a patient-derived xenograft model and a “dormant” T-cell signature associated with sensitivity to ICB is identified.
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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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