Functional Comparison of Engineered T Cells Carrying a Native TCR versus TCR-like Antibody–Based Chimeric Antigen Receptors Indicates Affinity/Avidity Thresholds

摘要: Adoptive transfer of Ag-specific T lymphocytes is an attractive form immunotherapy for cancers. However, acquiring sufficient numbers host-derived tumor-specific by selection and expansion challenging, as these cells may be rare or anergic. Using engineered can overcome this difficulty. Such generated using a chimeric Ag receptor based on common formats composed from Ag-recognition elements such αβ-TCR genes with the desired specificity, Ab variable domain fragments fused cell-signaling moieties. Combining recognition are Abs that recognize peptide-MHC. TCR-like mimic fine specificity TCRs exhibit both binding properties kinetics high-affinity Abs. In study, we compared functional expressing native low affinity chains high Ab-based CAR targeting same specificity. We isolated recognizing HLA-A2-WT1Db126 complexes constructed was transduced into cells. Comparative analysis revealed major differences in function CAR-T TCR toward antigenic complex. Whereas low-affinity maintained potent cytotoxic activity exhibited reduced loss These results suggest upper threshold TCR-based to mediate effective outcomes The rational design constructs need optimized up given achieve optimal cell function.