title: Somatic Mutations and Neoepitope Homology in Melanomas Treated with CTLA-4 Blockade.
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 the presence of somatic mutations is associated with benefit from checkpoint inhibition. 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 our previously published study of 64 melanoma patients treated with CTLA-4 blockade and a new dataset of RNA-Seq data from 24 of these patients. We found that the ability to accurately predict patient benefit did not increase as the analysis narrowed from somatic mutation burden, to inclusion of only those mutations predicted to be MHC class I neoantigens, to only including those neoantigens that were expressed or that had homology to pathogens. The only association between somatic mutation burden and response was found when examining samples obtained prior to treatment. Neoantigen and expressed neoantigen burden were also associated with response, but neither was more predictive than somatic mutation burden. Neither the previously described tetrapeptide signature nor an updated method to evaluate neoepitope homology to pathogens was more predictive than mutation burden. Cancer Immunol Res; 5(1); 84-91. ©2016 AACR.
authors.affiliation: Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Tavi
authors.initials: T
authors.lastname: Nathanson
authors.affiliation: Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Arun
authors.initials: A
authors.lastname: Ahuja
authors.affiliation: Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Alexander
authors.initials: A
authors.lastname: Rubinsteyn
authors.affiliation: Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Bulent Arman
authors.initials: BA
authors.lastname: Aksoy
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hellmann
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Broad Institute of MIT and Harvard, Boston, Massachusetts.|Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Diana
authors.initials: D
authors.lastname: Miao
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Broad Institute of MIT and Harvard, Boston, Massachusetts.|Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Van Allen
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Medicine, Weill Cornell Medical College, New York, New York.|Swim Across America-Ludwig Collaborative Research Laboratory, Immunology Program, Ludwig Center for Cancer Immunotherapy, New York, New York.
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Medicine, Weill Cornell Medical College, New York, New York.|Swim Across America-Ludwig Collaborative Research Laboratory, Immunology Program, Ludwig Center for Cancer Immunotherapy, New York, New York.
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. snyderca@mskcc.org.|Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Snyder
authors.affiliation: Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Jeff
authors.initials: J
authors.lastname: Hammerbacher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000276:immunology; D000074322:Antineoplastic Agents, Immunological / Q000627:therapeutic use; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D000939:Epitopes / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology* / Q000401:mortality; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D017386:Sequence Homology, Amino Acid; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; D000074322:Antineoplastic Agents, Immunological; D060908:CTLA-4 Antigen; D000939:Epitopes