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J Mol Med (Berl). 2003 Jan;81(1):43-50. Epub 2002 Nov 13.

HLA-A3 restricted mutant ras specific cytotoxic T-lymphocytes induced by vaccination with T-helper epitopes.

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Section for Immunotherapy, Department of Immunology, Norwegian Radium Hospital, University of Oslo, Montebello, 0310 Oslo, Norway.


Cytotoxic T-lymphocytes are one of the most important elements of the antitumor defense. Stimulation of cytotoxic T-lymphocytes outgrowth after immunization with mutant ras peptides is a desired goal since these cells may kill tumor cells in vivo. In this study we tested responding peripheral mononuclear cells from a patient with pancreatic adenocarcinoma who had received intradermal peptide vaccination with a mixture of 17-mer mutant ras peptides and granulocyte-macrophage colony-stimulating factor as an adjuvant. Responding peripheral T-cells were cloned by limiting dilution and several CD8(+) cytotoxic T-lymphocytes, specific for the K- RAS 12-Cys mutation were obtained. By using a panel of nonamer peptides containing the 12-Cys mutation and covering position 4-21 in the ras molecule, the 9-mer peptide which was actually recognized by the cytotoxic T-lymphocytes could be identified. HLA-A*0302 could be identified as the antigen-presenting molecule, and the amino acid sequence of the T-cell epitope carries the previously identified HLA-A*0302 binding motif. The nonamer peptide was contained within the vaccine peptide originally used for intradermal immunization of the patient. The cytotoxic T-lymphocytes were capable of killing target cells expressing HLA-A*0302 that coexpressed the K- RAS 12-Cys mutation after transfection. These data demonstrate that the peptide used for vaccination (17-mer) is processed and presented in vivo, and that generation of cytotoxic T-lymphocytes by vaccination with T-helper epitopes may be important for further development of specific immunotherapy of cancer patients.

[Indexed for MEDLINE]

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