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

Authors

  • Carsten Schaefer,

    1. Department of Pathology, University of Pittsburgh Cancer Institute, and University of Pittsburgh School of Medicine, Pittsburgh, PA
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  • Lisa H. Butterfield,

    1. Department of Pathology, University of Pittsburgh Cancer Institute, and University of Pittsburgh School of Medicine, Pittsburgh, PA
    2. Department of Medicine, University of Pittsburgh, Pittsburgh, PA
    3. Department of Surgery, University of Pittsburgh, Pittsburgh, PA
    4. Department of Immunology, University of Pittsburgh, Pittsburgh, PA
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  • Sandra Lee,

    1. Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, MA
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  • Grace G. Kim,

    1. Department of Pathology, University of Pittsburgh Cancer Institute, and University of Pittsburgh School of Medicine, Pittsburgh, PA
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  • Carmen Visus,

    1. Department of Pathology, University of Pittsburgh Cancer Institute, and University of Pittsburgh School of Medicine, Pittsburgh, PA
    2. Department of Pathology, University of Pittsburgh, Pittsburgh, PA
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  • Andreas Albers,

    1. Department of Pathology, University of Pittsburgh Cancer Institute, and University of Pittsburgh School of Medicine, Pittsburgh, PA
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  • John M. Kirkwood,

    1. Department of Pathology, University of Pittsburgh Cancer Institute, and University of Pittsburgh School of Medicine, Pittsburgh, PA
    2. Department of Medicine, University of Pittsburgh, Pittsburgh, PA
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  • Theresa L. Whiteside

    Corresponding author
    1. Department of Pathology, University of Pittsburgh Cancer Institute, and University of Pittsburgh School of Medicine, Pittsburgh, PA
    2. Department of Immunology, University of Pittsburgh, Pittsburgh, PA
    3. Department of Pathology, University of Pittsburgh, Pittsburgh, PA
    • Hillman Cancer Center, 5117 Centre Avenue, Suite 1.27, Pittsburgh, PA 15213
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    • Tel.: 412-624-0096, Fax: 412-624-0264


Abstract

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.

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