HLA-A*02 Major Histocompatibility Complex (MHC) allele
HLA-A*02 allele is expressed in class I Human MHC Leukocyte Antigens (HLA),that are cell surface receptors,presenting peptides to the immune system. If a non-self-peptide is recognized by cytotoxic T-cells in the blood,cell death will be initiated via apoptosis.
NY-ESO-1 protein
Peptides presented by MHC class I molecule,are usually between 7 and 11 amino acids,originating from proteins expressed by the cell. SLLMWITQV peptide differes from the New York esophageal squamous cell carcinoma 1 (NY-ESO-1 : UniProt – P78358) native SLLMWITQC peptide,whose protein is part of a well-characterized group of cancer/testis antigens (CTAs).
Normally,NY-ESO-1 expression is restricted to germ cells and placental cells. However it is also expressed in 82% of neuroblastomas and 46% of melanomas,as well as in many other solid tumors and hematological malignancies.
NY-ESO-1 (157-165) C165V peptide application
Class I HLA molecules of the cancerous cells cited above present peptides from NY-ESO-1 protein,including SLLMWITQC,that binds the binding cleft of the HLA-A*0201 complex. NY-ESO-1 being the most immunogenic among the CTA family members,its peptides constitute attractive targets for specific immunotherapies and the stimulation of human NY-ESO-1 specific CD8+ T cells.
In order to better stimulate specific cytotoxic T-cells in PBMCs and analyze by ELISPOT peptide epitope,specificity,and cytokine production,like IFN-γ,SLLMWITQV variant peptide was used,as it is known to have a higher affinity for the binding cleft of the HLA-A*0201 complex than the native peptide. Moreover,SLLMWITQV has been used with adjuvant in protein nanoparticles in order to study cell-mediated immune responses and is also used in clinical trial to study the immunological effects of vaccines containing NY-ESO-1 (157-165) C165V.
Nanoparticles have attracted considerable interest as cancer vaccine delivery vehicles for inducing sufficient CD8+ T cell-mediated immune responses to overcome the low immunogenicity of tumor microenvironments. Our studies described here are the first to examine the effects of clinically-tested human cancer-testis (CT) peptide epitopes within a synthetic nanoparticle. Specifically,we focused on two significant clinical CT targets,the HLA-A2 restricted epitopes of NY-ESO-1 and MAGE-A3,using a viral-mimetic packaging strategy. Our data shows that simultaneous delivery of a NY-ESO-1 epitope (SLLMWITQV) and CpG using the E2 subunit assembly of pyruvate dehydrogenase (E2 nanoparticle),resulted in a 25-fold increase in specific IFN-γ secretion in HLA-A2 transgenic mice. This translated to a 15-fold increase in lytic activity toward target cancer cells expressing the antigen. Immunization with a MAGE-A3 epitope (FLWGPRALV) delivered with CpG in E2 nanoparticles yielded an increase in specific IFN-γ secretion and cell lysis by 6-fold and 9-fold,respectively. Furthermore,combined delivery of NY-ESO-1 and MAGE-A3 antigens in E2 nanoparticles yielded an additive effect that increased lytic activity towards cells bearing NY-ESO-1+ and MAGE-A3+. Our investigations demonstrate that formulation of CT antigens within a nanoparticle can significantly enhance antigen-specific cell-mediated responses,and the combination of the two antigens in a vaccine can preserve the increased individual responses that are observed for each antigen alone.
2- Sommermeyer D.,Conrad H.,Kronig H.,Gelfort H.,Bernhard H. and Uckert W. International Journal of Cancer 132(6):1360-1367 (2012)
The cancer‐testis antigen NY‐ESO‐1 has been used as a target for different immunotherapies like vaccinations and adoptive transfer of antigen‐specific cytotoxic T cells,as it is expressed in various tumor types and has limited expression in normal cells. The in vitro generation of T cells with defined antigen specificity by T cell receptor (TCR) gene transfer is an established method to create cells for immunotherapy. However,an extensive characterization of TCR which are candidates for treatment of patients is crucial for successful therapies. The TCR has to be efficiently expressed,their affinity to the desired antigen should be high enough to recognize low amounts of endogenously processed peptides on tumor cells,and the TCR should not be cross‐reactive to other antigens. We characterized three NY‐ESO‐1 antigen‐reactive cytotoxic T lymphocyte clones which were generated by different approaches of T cell priming (autologous,allogeneic),and transferred their TCR into donor T cells for more extensive evaluations. Although one TCR most efficiently bound MHC‐multimers loaded with NY‐ESO‐1 peptide,T cells expressing this transgenic TCR were not able to recognize endogenously processed antigen. A second TCR recognized HLA‐A2 independent of the bound peptide beside its much stronger recognition of NY‐ESO‐1 bound to HLA‐A2. A third TCR displayed an intermediate but peptide‐specific performance in all functional assays and,therefore,is the most promising candidate TCR for further clinical development. Our data indicate that multiple parameters of TCR gene‐modified T cells have to be evaluated to identify an optimal TCR candidate for adoptive therapy.
3- Jäger E. et al. Int J Cancer. 84(5):506-510 (1999)
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)
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)
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)
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.
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