Induction of tumor-reactive cytotoxic T-lymphocytes using a peptide from NY-ESO-1 modified at the carboxy-terminus to enhance HLA-A2.1 binding affinity and stability in solution.
NY-ESO-1 is an attractive candidate tumor antigen for the development of immunotherapy for a wide variety of cancers. It is expressed in multiple types of tumors, but its normal tissue distribution is predominantly limited to the testes and ovaries; furthermore, both humoral and cellular immune responses can be mounted against this protein. Three overlapping HLA-A2.1-restricted T-cell epitopes have been identified within NY-ESO-1. In this investigation, the authors evaluated the in vitro immunogenicity of these peptides. From 2 of 12 HLA-A2.1+ patients with metastatic melanoma, peptide-reactive cytotoxic T-lymphocytes were generated using either NY-ESO-1:157-167 or NY-ESO-1:157-165 but not NY-ESO-1:155-163. Because NY-ESO-1:157-165 is a 9 amino acid peptide completely contained within NY-ESO-1:157-167, it seemed likely that this peptide was the minimal determinant, and thus it was selected for continued study. An amino acid substitution of C to V was introduced into NY-ESO-1:157-165 at P9 to attempt to improve its immunogenicity by enhancing its binding affinity to HLA-A2.1 and increasing its stability in solution, because the C residue is readily oxidized, leading to dimerization of the peptide. From 5 of 20 HLA-A2.1+ patients with metastatic melanoma, NY-ESO-1:157-165(165V) stimulated cytotoxic T-lymphocytes in vitro, which recognized peptide-pulsed target cells and HLA-A2.1+ NY-ESO-1+ tumor cells, suggesting that this peptide may be clinically valuable for the treatment of patients with NY-ESO-1+ tumors.
Bownds
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Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1502, USA.
Tong-On
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Rosenberg
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SA
Parkhurst
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M
D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008545:Melanoma / Q000276:immunology* / Q000556:secondary; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011506:Proteins / Q000276:immunology* / Q000378:metabolism; D012996:Solutions; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D015789:HLA-A2 Antigen; D008565:Membrane Proteins; D010446:Peptide Fragments; D011506:Proteins; D012996:Solutions