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Somatic Mutations and Neoepitope Homology in Melanomas Treated with CTLA-4 Blockade

View ORCID ProfileTavi Nathanson, View ORCID ProfileArun Ahuja, View ORCID ProfileAlexander Rubinsteyn, View ORCID ProfileBulent Arman Aksoy, Matthew D. Hellmann, Diana Miao, Eliezer Van Allen, Taha Merghoub, Jedd Wolchok, View ORCID ProfileAlexandra Snyder, View ORCID ProfileJeff Hammerbacher
doi: https://doi.org/10.1101/088286
Tavi Nathanson
Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
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Arun Ahuja
Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
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Alexander Rubinsteyn
Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
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Bulent Arman Aksoy
Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
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Matthew D. Hellmann
Department of Medicine, Memorial Sloan Kettering Cancer Center and Department of Medicine, Weill Cornell Medical College
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Diana Miao
Department of Medical Oncology, Dana-Farber Cancer Institute, Broad Institute of MIT and Harvard, Center for Cancer Precision Medicine, Dana-Farber Cancer Institute
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Eliezer Van Allen
Department of Medical Oncology, Dana-Farber Cancer Institute, Broad Institute of MIT and Harvard, Center for Cancer Precision Medicine, Dana-Farber Cancer Institute
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Taha Merghoub
Department of Medicine, Memorial Sloan Kettering Cancer Center and Department of Medicine, Weill Cornell Medical CollegeSwim Across America–Ludwig Collaborative Research Laboratory, Immunology Program, Ludwig Center for Cancer Immunotherapy
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Jedd Wolchok
Department of Medicine, Memorial Sloan Kettering Cancer Center and Department of Medicine, Weill Cornell Medical CollegeSwim Across America–Ludwig Collaborative Research Laboratory, Immunology Program, Ludwig Center for Cancer Immunotherapy
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Alexandra Snyder
Department of Medicine, Memorial Sloan Kettering Cancer Center and Department of Medicine, Weill Cornell Medical College
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Jeff Hammerbacher
Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
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Abstract

Immune checkpoint inhibitors are promising treatments for patients with a variety of malignancies. Toward understanding the determinants of response to immune checkpoint inhibitors, it was previously demonstrated that somatic mutation burden is associated with benefit and a hypothesis was posited that neoantigen homology to pathogens may in part explain the link between somatic mutations and response. To further examine this hypothesis, we reanalyzed cancer exome data obtained from a previously published study of 64 melanoma patients treated with CTLA-4 blockade and a new dataset of RNA-Seq data from 24 of those patients. We found that the predictive accuracy does not increase as analysis narrows from somatic mutation burden to predicted MHC Class I neoantigens, expressed neoantigens, or homology to pathogens. Further, the association between somatic mutation burden and response is only found when examining samples obtained prior to treatment. Neoantigen and expressed neoantigen burden are also associated with response, but neither is more predictive than somatic mutation burden. Neither the previously-described tetrapeptide signature nor an updated method to evaluate neoepitope homology to pathogens were more predictive than mutation burden.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted November 17, 2016.
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Somatic Mutations and Neoepitope Homology in Melanomas Treated with CTLA-4 Blockade
Tavi Nathanson, Arun Ahuja, Alexander Rubinsteyn, Bulent Arman Aksoy, Matthew D. Hellmann, Diana Miao, Eliezer Van Allen, Taha Merghoub, Jedd Wolchok, Alexandra Snyder, Jeff Hammerbacher
bioRxiv 088286; doi: https://doi.org/10.1101/088286
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Somatic Mutations and Neoepitope Homology in Melanomas Treated with CTLA-4 Blockade
Tavi Nathanson, Arun Ahuja, Alexander Rubinsteyn, Bulent Arman Aksoy, Matthew D. Hellmann, Diana Miao, Eliezer Van Allen, Taha Merghoub, Jedd Wolchok, Alexandra Snyder, Jeff Hammerbacher
bioRxiv 088286; doi: https://doi.org/10.1101/088286

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