Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells

Science. 2015 May 15;348(6236):803-8. doi: 10.1126/science.aaa3828. Epub 2015 Apr 2.

Abstract

T cell immunity directed against tumor-encoded amino acid substitutions occurs in some melanoma patients. This implicates missense mutations as a source of patient-specific neoantigens. However, a systematic evaluation of these putative neoantigens as targets of antitumor immunity is lacking. Moreover, it remains unknown whether vaccination can augment such responses. We found that a dendritic cell vaccine led to an increase in naturally occurring neoantigen-specific immunity and revealed previously undetected human leukocyte antigen (HLA) class I-restricted neoantigens in patients with advanced melanoma. The presentation of neoantigens by HLA-A*02:01 in human melanoma was confirmed by mass spectrometry. Vaccination promoted a diverse neoantigen-specific T cell receptor (TCR) repertoire in terms of both TCR-β usage and clonal composition. Our results demonstrate that vaccination directed at tumor-encoded amino acid substitutions broadens the antigenic breadth and clonal diversity of antitumor immunity.

Trial registration: ClinicalTrials.gov NCT00683670.

Publication types

  • Clinical Trial, Phase III
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution / immunology
  • Antigen Presentation
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / immunology*
  • Cancer Vaccines / immunology
  • Cancer Vaccines / therapeutic use*
  • Dendritic Cells / immunology
  • Dendritic Cells / transplantation*
  • HLA-A2 Antigen / genetics
  • HLA-A2 Antigen / immunology*
  • Humans
  • Immunotherapy, Active / methods*
  • Melanoma / genetics
  • Melanoma / immunology
  • Melanoma / therapy*
  • Monitoring, Immunologic
  • Mutation
  • Receptors, Antigen, T-Cell, alpha-beta / immunology
  • Skin Neoplasms / genetics
  • Skin Neoplasms / immunology
  • Skin Neoplasms / therapy*
  • T-Lymphocytes / immunology*

Substances

  • Antigens, Neoplasm
  • Cancer Vaccines
  • HLA-A*02:01 antigen
  • HLA-A2 Antigen
  • Receptors, Antigen, T-Cell, alpha-beta

Associated data

  • ClinicalTrials.gov/NCT00683670