Myeloma-specific multiple peptides able to generate cytotoxic T lymphocytes: a potential therapeutic application in multiple myeloma and other plasma cell disorders.

Abstract

The efficacy of peptide vaccines may be enhanced by stimulating immune cells with multiple peptides derived from distinct tumor-associated antigens. We have evaluated the heteroclitic XBP1-US(184-192) (YISPWILAV), heteroclitic XBP1-SP(367-375) (YLFPQLISV), native CD138(260-268) (GLVGLIFAV), and native CS1(239-247) (SLFVLGLFL) peptides, which have strong HLA-A2 affinity and immunogenicity in combination, for their ability to elicit multiple myeloma antigen-specific responses. Multipeptide-specific cytotoxic T lymphocytes (MP-CTL) were generated by the stimulation of CD3(+) T lymphocytes from HLA-A2(+) individuals with either autologous mature dendritic cells or T2 cells pulsed with a cocktail of these four peptides. The peptide cocktail did not compromise tumor antigen-specific activity of CTLs. MP-CTLs displayed increased total, effector memory (CCR7(-)CD45RO(+)), and activated (CD69(+)) CD3(+)CD8(+) T lymphocytes. In addition, MP-CTL showed IFN-γ production, cell proliferation, and cytotoxicity against HLA-A2(+) multiple myeloma cells, including cells of HLA-A2(+) patients with multiple myeloma. Importantly, MP-CTLs showed specific responses in functional assays to each relevant peptide but not to an irrelevant HLA-A2-specific CMV pp65 (NLVPMVATV) peptide. These results highlight the potential therapeutic application of vaccination with a cocktail of HLA-A2-specific peptides to induce CTLs with a broad spectrum of immune responses against multiple myeloma antigens.