The general idea of this revised application is to develop a prostate cancer vaccine targeted to the reverse transcriptase of telomerase (TRT), a unique ribonucleoprotein that mediates RNA-dependent synthesis of telomeric DNA. During the past year, the applicant has obtained compelling evidence that this idea is valid and worth pursuing. The main goals are to demonstrate that peptides of human telomerase are immunogenic 1) in vitro for lymphocytes of prostate cancer patients, and 2) in vivo in mice transgenic for the human HLA-A2.1 molecule and in mice bearing a model prostate cancer. These objectives will be pursued in four aims. (1) Identification and testing HLA-A2.1 restricted human (h)TRT peptides. (2) Optimization of peptide immunogenicity in vitro of fusion (hTRT) peptides with natural or artificial signal sequences and targeted point mutations to increase the avidity of MHC binding. (3) Induction of CTL in prostate cancer patients, in which the applicant will assess whether exposure to cancer modifies the available peripheral repertoire (e.g., by tolerance or clonal anergy) and diminishes the precursor frequency for hTRT peptides and their ability to undergo expansion upon immunization. The applicant will study HLA-A2.1+ individuals with clinical/histological diagnosis of prostate cancer. And (4) In vivo immunogenicity of telomerase peptides using two transgenic mouse models, one for the human HLA-A2.1 molecule and the other for the simian virus (SV) 40 large T antigen where SV40 Tag is responsible for prostate cancer. Using the first transgenic model he will test the ability of hTRT peptides to induce HLA-A2.1-restricted CTL responses. Using the second transgenic model, and using murine TRT peptides, he will answer the question """"""""Does presence of prostate tumor affect immunization against telomerase peptides?""""""""
| Cortez-Gonzalez, Xochitl; Sidney, John; Adotevi, Olivier et al. (2006) Immunogenic HLA-B7-restricted peptides of hTRT. Int Immunol 18:1707-18 |
| Zanetti, Maurizio; Hernandez, Xavier; Langlade-Demoyen, Pierre (2005) Telomerase reverse transcriptase as target for anti-tumor T cell responses in humans. Springer Semin Immunopathol 27:87-104 |
| Hernandez, Javier; Schoeder, Kim; Blondelle, Sylvie E et al. (2004) Antigenicity and immunogenicity of peptide analogues of a low affinity peptide of the human telomerase reverse transcriptase tumor antigen. Eur J Immunol 34:2331-41 |
| Hernandez, Javier; Garcia-Pons, Francisco; Lone, Yu Chun et al. (2002) 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. Proc Natl Acad Sci U S A 99:12275-80 |
