title: Phenotypic and functional maturation of tumor antigen-reactive CD8+ T lymphocytes in patients undergoing multiple course peptide vaccination.
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.
authors.affiliation: Surgery Branch, National Cancer Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Powell
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
mesh_terms: D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D002454:Cell Differentiation; D003601:Cytotoxicity Tests, Immunologic; D004306:Dose-Response Relationship, Immunologic; D015234:HLA-A Antigens / Q000276:immunology; D015789:HLA-A2 Antigen; D006801:Humans; D018655:Lymphocyte Count; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000276:immunology*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000276:immunology*; D010641:Phenotype; D014611:Vaccination / Q000379:methods; D022223:Vaccines, Subunit / Q000008:administration & dosage*; D058951:gp100 Melanoma Antigen
chemical_list: D019496:Cancer Vaccines; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D022223:Vaccines, Subunit; D058951:gp100 Melanoma Antigen