HER-2/neuand hTERT Cryptic Epitopes as Novel Targets for Broad Spectrum Tumor Immunotherapy

Abstract

Tolerance to tumor-nonmutated self proteins represents a major obstacle for successful cancer immunotherapy. Since this tolerance primarily concerns dominant epitopes, we hypothesized that targeting cryptic epitopes that have a low affinity for HLA could be an efficient strategy to breach the tolerance to tumor Ags. Using the P1Y heteroclitic peptide approach, we identified low affinity cryptic HLA-A*0201-restricted epitopes derived from two widely expressed tumor Ags, HER-2/neu and hTERT. The P1Y variants of four HER-2/neu (neu391, neu402, neu466, neu650)- and two hTERT (hTERT572 and hTERT988)-derived low affinity peptides exhibited strong affinity for HLA-A*0201 and stimulated specific CTL from healthy donor PBMCs. These CTL specifically recognized HER-2/neu- and hTERT-expressing tumor cells of various histological origins. In vivo studies showed that HLA-A*0201 transgenic HHD mice vaccinated with the P1Y variant peptides generated CTL that specifically lysed Ag-expressing tumor cells, thus recognizing the cognate endogenous Ags. These results suggest that heteroclitic variants of low affinity, cryptic epitopes of widely expressed tumor Ags may serve as valid tools for tumor immunotherapy.

Identification and Characterization of the Immunodominant Rat HER-2/neu MHC Class I Epitope Presented by Spontaneous Mammary Tumors from HER-2/neu-Transgenic Mice

“…This is not surprising, because vaccinating mice or patients with solely MHC-I tumor epitopes has produced only modest results in most studies. For some Ags, altering the wild-type MHC-I epitope so that it binds more strongly to MHC and/or demonstrates greater recognition in vitro by Ag-specific T cells improves the immunization potential and the clinical outcome (54,(65)(66)(67). In this study, we show that vaccinating FVB/N mice with dendritic cells pulsed with a heteroclitic variant of the wild-type epitope also induces improved protection against tumors that express the natural RNEU 420 -429 epitope as compared with immunization with the RNEU 420 -429 epitope itself.…”

Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study

“…It is well established that T cells of the human immune system can recognise hTERT peptides, and a number of HLA-class I and class II epitopes have been characterised (Vonderheide et al, 1999;Minev et al, 2000;Arai et al, 2001;Vonderheide et al, 2001;Hernandez et al, 2002;Scardino et al, 2002;Schroers et al, 2002Schroers et al, , 2003Gross et al, 2004). Recently it has also been reported that telomerase-specific CD4 þ and CD8 þ T-cell responses are induced upon vaccination with hTERT-transfected dendritic cells (Su et al, 2005).…”

Cytotoxic T cell responses to human telomerase reverse transcriptase in patients with hepatocellular carcinoma

“…[7][8][9][10] Recently, several results regarding hTERT-specific cytotoxic T cell (CTL) responses were reported for humans and mice. [11][12][13][14][15][16][17][18][19][20] These reports revealed that hTERT-specific CTLs induced by stimulation with peptides or DNA-based immunization kill cancer cell lines that have high levels of hTERT, suggesting that hTERT-reactive T cell clones are not deleted from the human T cell repertoire and that hTERT may be a useful tumor-specific antigen as a target for T-cell-based immunotherapy for cancers. However, the existence of hTERT-specific CTLs and the relationship between immunological…”