Identification of a human telomerase reverse transcriptase peptide of low affinity for HLA A2.1 that induces cytotoxic T lymphocytes and mediates lysis of tumor cells

Abstract

Telomerase reverse transcriptase (TRT) is a tumor-associated antigen expressed in the vast majority of human tumors and is presently one of the most promising target candidates for a therapeutic cancer vaccine. TRT is also expressed at low level in selected tissues and should be considered a self antigen. In the present study we sought to develop cytotoxic T lymphocytes (CTL) responses directed against human (h)TRT peptides with low relative affinity for which the available repertoire is to be preferentially spared from tolerance. This was accomplished by using analogue peptides of hTRT whose relative affinity for the MHC was increased by a targeted (3 Tyr) substitution in position one. By immunizing HLA A2.1 transgenic mice with these analogue peptides, we identified one such low relative affinity peptide (p572) that is endogenously processed and presented by HLA A2.1 in tumor cells, and is recognized by specific CTL. We used the highly immunogenic analogue peptide to successfully induce TRTspecific CTL in cancer patients and normal donors. CTL against p572-lysed human and mouse tumor cells but not activated autologous B cells. This peptide represents, therefore, an important candidate component of a cancer vaccine based on a TRT substrate and validates the strategy of targeting peptides with low affinity for the MHC for cancer immunotherapy.

Artificial Antigen-Presenting Cells Transduced with Telomerase Efficiently Expand Epitope-Specific, Human Leukocyte Antigen–Restricted Cytotoxic T Cells

“…The therapeutic strategies under investigation include functional inhibition by genetic and pharmacologic approaches (15,16,18,19) as well as immunotherapy (20). hTERT contains several HLA-restricted-binding motifs that have been used to generate tumoricidal CTLs (21)(22)(23). Minev et al found that immunization of patients with prostate cancer with two HLA-A*0201 + -restricted peptides from hTERT, p540 (ILAKFLHWL) and p865 (RLVDDFLLV), developed hTERT-specific CTLs that specifically lysed a variety of HLA-A*0201 + cancer cell lines (24).…”

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).…”

Prospects and challenges of building a cancer vaccine targeting telomerase

“…These include epitopes restricted to HLA-A2 as well as HLA-A1, -A3, -A24, and -B7 [41,[48][49][50][51][52][53][54][55][56]. More than 90% of humans express at least one of these five MHC class I alleles.…”

“…Classically considered poorly immunogenic, low-affinity epitopes can induce robust CTL responses after modification from wild type sequence, for example, by changing position 1 of HLA-A2-restricted peptide epitopes to tyrosine [60]. Two such low-affinity HLA-A2-restricted epitopes derived from hTERT are 572Y (YLFFYRKSV) and 988Y (YLQVNSLQTV) [50,51] and each exhibits strong affinity for HLA-A2 and stimulates specific CTL in vitro. These CTL specifically lyse hTERT-expressing tumor cells of various histologies but not HLA-A2-negative or hTERT-negative tumors [50,51].…”