Phenotypic and functional maturation of tumor antigen-reactive CD8+ T lymphocytes in patients undergoing multiple course peptide vaccination

J Immunother. Jan-Feb 2004;27(1):36-47. doi: 10.1097/00002371-200401000-00004.

Abstract

Successful immunotherapy with peptide vaccines depends on the in vivo generation of sufficient numbers of anti-tumor T cells with appropriate phenotypic and functional characteristics to mediate tumor destruction. Herein, we report the induction of high frequencies of circulating CD8+ T cells (4.8% to 38.1%) directed against the native gp100:209-217 peptide derived from the gp100 melanoma-melanocyte tumor antigen in five HLA-A*0201 patients at high risk of recurrence of melanoma after multiple courses of immunization with modified gp100:209-217(210M) peptide in IFA. Longitudinal peripheral blood mononuclear cell (PBMC) analysis revealed a phenotypic shift of native peptide-specific CD8+ T cells from an early effector to an effector memory (CD27- CD28- CD62L- CD45RO+) phenotype with repeated immunizations and functional maturation that correlated with gp100:209-217 peptide-specific T-cell precursor frequencies. Postimmunization PBMC exhibited direct ex vivo recognition of melanoma cell lines in ELISPOT analysis, showed lytic capability against peptide-pulsed target cells, and proliferated in response to native peptide stimulation. One year after final immunization, circulating vaccine-specific CD8+ T cells persisted in patients' PBMC with a maintained effector memory phenotype. The results herein demonstrate the efficacy of a multiple course peptide-immunization strategy for the generation of high frequencies of tumor antigen-specific T cells in vivo, and further show that continued peptide immunization results in the escalating generation of functionally mature, tumor-reactive effector memory CD8+ T lymphocytes.

Publication types

  • Evaluation Study

MeSH terms

  • Adult
  • Aged
  • CD8-Positive T-Lymphocytes / immunology*
  • Cancer Vaccines / administration & dosage*
  • Cancer Vaccines / immunology
  • Cell Differentiation
  • Cytotoxicity Tests, Immunologic
  • Dose-Response Relationship, Immunologic
  • HLA-A Antigens / immunology
  • HLA-A2 Antigen
  • Humans
  • Lymphocyte Count
  • Melanoma / immunology
  • Melanoma / therapy*
  • Membrane Glycoproteins / immunology*
  • Middle Aged
  • Neoplasm Proteins / immunology*
  • Phenotype
  • Vaccination / methods
  • Vaccines, Subunit / administration & dosage*
  • gp100 Melanoma Antigen

Substances

  • Cancer Vaccines
  • HLA-A Antigens
  • HLA-A*02:01 antigen
  • HLA-A2 Antigen
  • Membrane Glycoproteins
  • Neoplasm Proteins
  • PMEL protein, human
  • Vaccines, Subunit
  • gp100 Melanoma Antigen