PT - JOURNAL ARTICLE AU - Tavi Nathanson AU - Arun Ahuja AU - Alexander Rubinsteyn AU - Bulent Arman Aksoy AU - Matthew D. Hellmann AU - Diana Miao AU - Eliezer Van Allen AU - Taha Merghoub AU - Jedd Wolchok AU - Alexandra Snyder AU - Jeff Hammerbacher TI - Somatic Mutations and Neoepitope Homology in Melanomas Treated with CTLA-4 Blockade AID - 10.1101/088286 DP - 2016 Jan 01 TA - bioRxiv PG - 088286 4099 - http://biorxiv.org/content/early/2016/11/17/088286.short 4100 - http://biorxiv.org/content/early/2016/11/17/088286.full AB - 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.