NY-ESO-1 (123-137) DRB1*04:01 – LKEFTVSGNILTIRL – General analogue epitope of tumor cells
NY-ESO-1 (123-137) DRB1*04:01 is an epitope analogue of the New York esophageal squamous cell carcinoma-1, also named cancer testis. NY-ESO-1 is expressed in 82% of neuroblastomas and 46% of melanomas but also in many others solid tumors and hematological malignancies. That’s why, NY-ESO-1 peptides are attractive targets for specific immunotherapies and for the stimulation of human NY-ESO-1 specific CD8+ T cells.
Applications of NY-ESO-1 (123-137) DRB1*04:01
Results of studies suggest after stimulation of NY-ESO-1 (123-137) DRB1*04:01 specific T cells and IFN- ELISPOT and chronium release assays that NY-ESO-1 (123-137) DRB1*04:01 can be an immunogenic epitope encoded by NY-ESO-1. NY-ESO-1 (123-137) DRB1*04:01 contains epitope capable of binding HLA-DR molecules.
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1- Zarour H. M., Storkus W. J., Brusic V., Williams E. and Kirkwood J. M. Cancer research 60:4946-4952 (2000)
The NY-ESO-1 gene is expressed by a range of human tumors and encodes HLA-A2-restricted melanoma peptides recognized by CD8+ CTLs. Here we report that the NY-ESO-1 gene also encodes two overlapping, but non-cross-reactive, HLA-DRB1*0401-presented peptides that are recognized by CD4+ T cells. The NY-ESO-1119–143 peptide was able to induce specific CD4+ T cells in vitro from both an HLA-DRB1*0401+ normal donor and an HLA-DRB1*0401+ patient with melanoma. Bulk and cloned CD4+ T cells produced IFN-γ specifically in response to, and also lysed, T2.DR4 cells pulsed with peptide NY-ESO-1119–143 and the autologous tumor cell line, but not a DRB1*0401+ melanoma cell line that does not express NY-ESO-1. Interestingly, the NY-ESO119–143 peptide contains two overlapping putative “core” epitopes recognized by non-cross-reactive anti-NY-ESO-1119–143 CD4+ T-cell clones. Taken together, these data support the use of this novel DR4-restricted tumor peptide, NY-ESO-1119–143, or its two “sub-epitopes” in immunotherapeutic trials designed to generate or enhance specific CD4+ T-cell responses against tumors expressing NY-ESO-1 in vivo.
2- Kudela P., et al. J. Immuno. 179:7932-7940 (2007)
TCRs exhibit a high degree of speciﬁcity but may also recognize multiple and distinct peptide-MHC complexes, illustrating the so-called cross-reactivity of TCR-peptide-MHC recognition. In this study, we report the ﬁrst evidence of CD4+T cells recognizing the same tumor peptide-epitope from NY-ESO-1, in the context of multiple HLA-DR and HLA-DP molecules. These cross-reactive CD4+T cells recognized not only autologous but also allogenic dendritic cells previously loaded with the relevant protein (i.e., the normally processed and presented epitope). Using clonotypic real-time RT-PCR, we have detected low frequencies of CD4+T cells expressing one cross-reactive TCR from circulating CD4+T cells of patients with stage IV melanoma either spontaneously or after immunization but not in normal donors. The maintenance of cross-reactive tumor Ag-speciﬁc CD4+T cells in PBLs of cancer patients required the presence of tumor Ag/epitope in the context of the MHC molecule used to prime the Ag-speciﬁc CD4+T cells. Our ﬁndings have signiﬁcant implications for the optimization of TCR gene transfer immunotherapies widely applicable to cancer patients.
3- Jäger E. et al. Int J Cancer. 84(5):506-510 (1999)
Humoral immune responses of cancer patients against “Cancer-Testis” antigen NY-ESO-1: correlation with clinical events
Humoral immune responses against the “Cancer-Testis” (CT) antigen NY-ESO-1 are frequently observed in patients with NY-ESO-1 expressing tumors. This is in contrast to other known tumor antigens (TA) defined by antibody or cytotoxic T cell (CTL) reactivity, i.e., MAGE-1, MAGE-3, SSX2, Melan A, and tyrosinase. No NY-ESO-1 antibody has been detected in healthy controls and patients with NY-ESO-1 negative tumors. In this study, we have assessed the NY-ESO-1 serum antibody response in patients with NY-ESO-1 positive tumors of different histological types and stages using Western blotting and an ELISA. Of the 12 patients analyzed, 10 had demonstrable NY-ESO-1 antibodies at the start of the study. All patients were followed for changes in NY-ESO-1 antibody titers during the course of tumor treatment and clinical evolution. In 4 patients, an increase of NY-ESO-1 antibody titer was observed with progression of disease or extensive tumor necrosis under treatment. One patient showed a stable NY-ESO-1 antibody titer over 3 years along with gradual regression of a large tumor mass. In 5 patients, a decrease of NY-ESO-1 antibody was detected: in 1 patient after curative tumor resection, in 3 patients with partial regression of metastatic disease under chemo- and immunotherapy, and in another patient with a NY-ESO-1 negative tumor relapse. Our results indicate that the induction and maintenance of NY-ESO-1 antibody is dependent on the presence of NY-ESO-1 expressing tumors. Furthermore, changes in NY-ESO-1 antibody titers correlate with the evolution of NY-ESO-1 positive disease.
4- Purbhoo M. A. et al. J Immunol. 176(12):7308-7316 (2006)
Quantifying and imaging NY-ESO-1/LAGE-1-derived epitopes on tumor cells using high affinity T cell receptors
Presentation of intracellular tumor-associated Ags (TAAs) in the context of HLA class I molecules offers unique cancer-specific cell surface markers for the identification and targeting of tumor cells. For most peptide Ags, the levels of and variations in cell surface presentation remain unknown, yet these parameters are of crucial importance when considering specific TAAs as targets for anticancer therapy. Here we use a soluble TCR with picomolar affinity for the HLA-A2-restricted 157-165 epitope of the NY-ESO-1 and LAGE-1 TAAs to investigate presentation of this immunodominant epitope on the surface of a variety of cancer cells. By single molecule fluorescence microscopy, we directly visualize HLA-peptide presentation for the first time, demonstrating that NY-ESO-1/LAGE-1-positive tumor cells present 10-50 NY-ESO-1/LAGE-1(157-165) epitopes per cell.
5- Jäger E. et al. Proc Natl Acad Sci U S A. 97(22):12198-12203 (2000)
Induction of primary NY-ESO-1 immunity: CD8+ T lymphocyte and antibody responses in peptide-vaccinated patients with NY-ESO-1+ cancers
Cancer-testis antigen NY-ESO-1 is one of the most immunogenic tumor antigens defined to date. Spontaneous humoral and CD8+ T-cell responses to NY-ESO-1 are detected in 40-50% of patients with advanced NY-ESO-1-expressing tumors. A clinical trial was initiated to study the immunological effects of intradermal vaccination with 3 HLA-A2-binding NY-ESO-1 peptides in 12 patients with metastatic NY-ESO-1-expressing cancers. Seven patients were NY-ESO-1 serum antibody negative, and five patients were NY-ESO-1 serum antibody positive at the outset of the study. Primary peptide-specific CD8+ T-cell reactions and delayed-type hypersensitivity responses were generated in four of seven NY-ESO-1 antibody-negative patients. Induction of a specific CD8+ T-cell response to NY-ESO-1 in immunized antibody-negative patients was associated with disease stabilization and objective regression of single metastases. NY-ESO-1 antibody-positive patients did not develop significant changes in baseline NY-ESO-1-specific T-cell reactivity. However, stabilization of disease and regression of individual metastases were observed in three of five immunized patients. These results demonstrate that primary NY-ESO-1-specific CD8+ T-cell responses can be induced by intradermal immunization with NY-ESO-1 peptides, and that immunization with NY-ESO-1 may have the potential to alter the natural course of NY-ESO-1-expressing tumors.
6- Valmori D. et al. Cancer Res. 60(16):4499-4506 (2000)
Naturally occurring human lymphocyte antigen-A2 restricted CD8+ T-cell response to the cancer testis antigen NY-ESO-1 in melanoma patients
Cancer testis (CT) antigens are particularly interesting candidates for cancer vaccines. However, T-cell reactivity to CT antigens has been detected only occasionally in cancer patients, even after vaccination. A new group of CT antigens has been recently identified using the SEREX technique based on immunoscreening of tumor cDNA expression libraries with autologous sera. We have used fluorescent HLA-A2/peptide tetramers containing an optimized antigenic peptide to directly identify HLA-A2-restricted CD8+ T cells specific for the SEREX-defined CT antigen NY-ESO-1 in melanoma patients. High frequencies of NY-ESO-1-specific CD8+ T cells were readily detected in peptide-stimulated peripheral blood mononuclear cells as well as in lymphocytes infiltrating melanoma lesions from patients with measurable antibody responses to NY-ESO-1. NY-ESO-1-specific CD8+ T cells were also detectable in peptide-stimulated peripheral blood mononuclear cells from some seronegative patients. Whereas the frequencies of NY-ESO-1-specific CD8+ T cells in circulating lymphocytes were usually below the limit of detection by tetramer staining, the presence of NY-ESO-1 CD8+ T cells displaying a memory phenotype was clearly detectable ex vivo in blood from a seropositive patient over an extended period of time. These results indicate that sustained CD8+ T-cell responses to CT antigens can naturally occur both locally and systemically in melanoma patients.