Function but not phenotype of melanoma peptide-specific CD8+ T cells correlate with survival in a multiepitope peptide vaccine trial (ECOG 1696)

• Published in: International journal of cancer Vol. 131; no. 4; pp. 874 - 884
• Main Authors: Schaefer, Carsten, Butterfield, Lisa H., Lee, Sandra, Kim, Grace G., Visus, Carmen, Albers, Andreas, Kirkwood, John M., Whiteside, Theresa L.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.08.2012; Wiley-Blackwell; Wiley Subscription Services, Inc
• Subjects: Amino Acid Sequence; Biological and medical sciences; Cancer; Cancer Vaccines - therapeutic use; CD8+ T cells; CD8-Positive T-Lymphocytes - immunology; Dermatology; Enzyme-Linked Immunosorbent Assay; Epitopes - chemistry; Epitopes - immunology; Flow Cytometry; Genotype & phenotype; Humans; immune monitoring; Immunophenotyping; Interferon-gamma - immunology; Lymphocytes; Medical research; Medical sciences; Melanoma; Melanoma - immunology; Melanoma - therapy; Neoplasm Proteins - chemistry; Neoplasm Proteins - immunology; Peptide Fragments - chemistry; Peptide Fragments - immunology; peptide-based vaccine; Peptides; Survival Analysis; tetramer; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Vaccines; Peptides; melanoma; Vaccine; Malignant tumor; immune monitoring; T cells; Survival; Phenotype; Cancerology; Surveillance; Tetramer; CD8; Malignant melanoma; peptide-based vaccine; Clinical trial; Cancer; CD8 T lymphocyte
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.26481

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.