Researchers at the UCLA Department of Microbiology, Immunology, and Molecular Genetics have isolated T cell receptors (TCRs) specific for NY-ESO-1 epitopes presented by four MHC molecules, and developed novel approaches to extend TCR gene therapies targeting NY-ESO-1 using these TCRs.
The αβ T cell receptor (TCR) determines the unique specificity of each nascent T cell. Upon assembly with CD3 signaling proteins on the T cell surface, the TCR surveils peptide ligands presented by major histocompatibility complex (MHC) molecules on the surface of nucleated cells. The specificity of the TCR for a peptide-MHC complex is determined by both the presenting MHC molecule and the presented peptide. Infected and cancerous cells present peptides that are recognized by CD8+ T cells as foreign or aberrant, resulting in T cell-mediated killing. Tumor-specific TCR gene transfer enables specific and potent immune targeting of tumor antigens. Due to the prevalence of the HLA-A2 major MHC, the majority of TCR gene therapy trials targeting public antigens have employed HLA-A2-restricted TCRs, limiting this approach to patients expressing HLA-A2 allele. Therefore, there is a need for broad and safe application of public antigen-targeted TCR gene therapies.
The NY-ESO-1 is a tumor-specific, immunogenic public antigen that is expressed across an array of tumor types, but it is susceptible to escape when targeted through a single HLA subtype. To broaden the clinical utility of NY-ESO-1 as a TCR gene therapy target, researchers at UCLA have identified novel TCRs that target NY-ESO-1 epitopes presented by common MHC alleles other than HLA-A2. These researchers propose that targeting multiple NY-ESO-1 epitopes will enable treatment of a larger patient set and may render treatment more robust toward tumor escape.