Recent research suggests that high-peptide MHC affinities of targeted epitopes are required for complete tumor eradication and tumor stroma destruction by specific T cells, presumably through the formation of stable synapses between the APCs and the effector T cells that are necessary for optimal stimulation of the latter ( 6). Obviously, the vaccine peptide needs to be presented on the targeted tumor cells at sufficient expression levels, but also peptide-MHC affinity appears to be a decisive factor for the immunogenic potential ( 3– 7). Selecting the right epitope is a crucial step in the design of an effective vaccine. Many variables in the design of peptide vaccination, such as type and length of the peptides, loading of one or multiple peptides on APCs or route of administration could potentially attribute to these disappointing observations.
The peptides administered to the patient mimic the epitopes presented on the target cells when associated with the restricting MHC and would thus be capable of inducing relevant immune responses.įor immunotherapy of cancer, various clinical applications in the past decades provided ample evidence of the feasibility, safety, and immunogenicity of this type of vaccine however, the efficacy has mostly been limited ( 1, 2). In the treatment of cancer and the prevention of infectious diseases, the use of therapeutic or prophylactic peptide vaccines can be a successful method to specifically direct the immune system against the right targets. These CPLs could improve the therapeutic outcome of vaccination strategies or can be used for ex vivo enrichment and faster expansion of Ag-specific T cells for transfer into patients. Eventually, we were able to construct a toolbox of preferred nonproteogenic residues with which practically any given HLA-A*02 restricted epitope can be readily optimized. The best CPLs displayed enhanced affinity for MHC, increasing MHC stability and prolonging recognition by Ag-specific T cells and, most importantly, they induced accelerated expansion of antitumor T cell frequencies in vitro and in vivo as compared with the native epitope. The crystal structure of one of the CPLs in complex with HLA-A*0201 revealed the molecular interactions likely responsible for improved binding. With this approach, we designed CPLs of viral epitopes, of melanoma-associated Ags, and of the minor histocompatibility Ag UTA2-1, which is currently being evaluated for its antileukemic activity in clinical dendritic cell vaccination trials. We screened more than 90 nonproteogenic, synthetic amino acids through a range of epitopes and tested more than 3000 chemically enhanced altered peptide ligands (CPLs) for binding affinity to HLA-A*0201. In thus study, we show that the MHC binding and consequent T cell reactivity against several HLA-A*02 restricted epitopes can be further improved through the incorporation of nonproteogenic amino acids at primary and secondary anchor positions.
Virus or tumor Ag–derived peptides that are displayed by MHC class I molecules are attractive starting points for vaccine development because they induce strong protective and therapeutic cytotoxic T cell responses.
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