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

Cancer Immunol Res. 2017 Jan;5(1):84-91. doi: 10.1158/2326-6066.CIR-16-0019. Epub 2016 Dec 12.

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.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Amino Acid Sequence
  • Antigens, Neoplasm / genetics*
  • Antigens, Neoplasm / immunology
  • Antineoplastic Agents, Immunological / therapeutic use
  • CTLA-4 Antigen / antagonists & inhibitors*
  • Epitopes / chemistry
  • Epitopes / genetics*
  • Epitopes / immunology*
  • Female
  • Humans
  • Male
  • Melanoma / drug therapy
  • Melanoma / genetics*
  • Melanoma / immunology*
  • Melanoma / mortality
  • Middle Aged
  • Mutation*
  • Prognosis
  • Sequence Homology, Amino Acid
  • Treatment Outcome

Substances

  • Antigens, Neoplasm
  • Antineoplastic Agents, Immunological
  • CTLA-4 Antigen
  • Epitopes