Function but not phenotype of melanoma peptide-specific CD8(+)  T cells correlate with survival in a multiepitope peptide vaccine trial (ECOG 1696).
ECOG 1696 was a Phase II multi-center trial testing vaccination with melanoma peptides, gp100, MART-1 and tyrosinase delivered alone, with GM-CSF, IFN-α2b or both cytokines to HLA-A2(+)  patients with metastatic melanoma. Here, the frequency of circulating CD8(+) tetramer(+)  (tet(+) ) T cells and maturation stages of responding T cells were serially monitored and compared with baseline values in a subset of patients (n = 37) from this trial. Multiparameter flow cytometry was used to measure the frequency of CD8(+)  T cells specific for gp100, MART-1, tyrosinase and influenza (FLU) peptides. Expression of CD45RA/CCR7 on CD8(+) tet(+)  T cells and CD25, CD27, CD28 on all circulating T cells was determined. Vaccine-induced changes in the CD8(+) tet(+)  T cell frequency and phenotype were compared with results of IFN-γ ELISPOT assays and with clinical responses. The frequency of CD8(+) tet(+)  T cells in the circulation was increased for the melanoma peptides (p < 0.03-0.0001) but not for FLU (p < 0.9). Only gp100- and MART-1-specific T cells differentiated to CD45RA(+) CCR7(-)  effector/memory T cells. In contrast to the IFN-γ ELISPOT frequency, previously correlated with overall survival (Kirkwood et al., Clin Cancer Res 2009;15:1443-51), neither the frequency nor differentiation stage of CD8(+) tet(+)  T cells correlated with clinical responses. Delivery of GM-CSF and/or IFN-α2b had no effects on the frequency or differentiation of CD8(+) tet(+) , CD8+ or CD4+ T cells. Phenotypic analyses of CD8(+) tet(+)  T cells did not correlate with clinical responses to the vaccine, indicating that functional assessments of peptide-specific T cells are preferable for monitoring of anti-tumor vaccines.
Department of Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Carsten
C
Schaefer
Lisa H
LH
Butterfield
Sandra
S
Lee
Grace G
GG
Kim
Carmen
C
Visus
Andreas
A
Albers
John M
JM
Kirkwood
Theresa L
TL
Whiteside
D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000276:immunology; D008545:Melanoma / Q000276:immunology* / Q000628:therapy*; D009363:Neoplasm Proteins / Q000737:chemistry / Q000276:immunology*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D016019:Survival Analysis
D019496:Cancer Vaccines; D000939:Epitopes; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D007371:Interferon-gamma