DNA fusion gene vaccines induce cytotoxic T-cell attack on naturally processed peptides of human prostate-specific membrane antigen.

Abstract:

:For long-term attack on tumor cells in patients with prostate cancer, induction of cytolytic T cells is desirable. Several lineage-specific target proteins are known and algorithms have identified candidate MHC class I-binding peptides, particularly for HLA-A*0201. We have designed tolerance-breaking DNA fusion vaccines incorporating a domain of tetanus toxin fused to candidate tumor-derived peptide sequences. Using three separate peptide sequences from prostate-specific membrane antigen (PSMA) (peptides PSMA(27) , PSMA(663) , and PSMA(711) ), this vaccine design induced high levels of CD8(+) T cells against each peptide in a HLA-A(*) 0201 preclinical model. In contrast, the full-length PSMA sequence containing all three epitopes was poorly immunogenic. Induced T cells were cytotoxic against peptide-loaded tumor cells, but only those against PSMA(27) or PSMA(663) peptides, and not PSMA(711) , were able to kill tumor cells expressing endogenous PSMA. Cytotoxicity was also evident in vivo. The preclinical model provides a powerful tool for generating CD8(+) T cells able to predict whether target cells can process and present peptides, essential for planning peptide vaccine-based clinical trials.

journal_name

Eur J Immunol

authors

Vittes GE,Harden EL,Ottensmeier CH,Rice J,Stevenson FK

doi

10.1002/eji.201141518

subject

Has Abstract

pub_date

2011-08-01 00:00:00

pages

2447-56

issue

8

eissn

0014-2980

issn

1521-4141

journal_volume

41

pub_type

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