Modern Laboratory Test-Systems as Platforms for Validation of Clinically Promising T-Cell Receptors

Abstract— The development of therapeutic antigen-specific T-cell receptors (TCRs) requires comprehensive preclinical validation of their functional activity. One of the approaches in the development of new drugs for cell therapy based on antigen-specific T lymphocytes is the modification of autologous T lymphocytes with endogenous T-cell receptors. The present work reviews modern laboratory platforms used to assess key TCR characteristics: immunological synapse formation, specificity and affinity of antigen binding, activation of signaling pathways, cytokine production and cytotoxic potential. Particular attention is paid to the creation of model T-cell lines expressing transgenic TCRs, optimization of HLA context of target cells and application of multiparametric technologies for immune response analysis. The prospects of using 3D organoid models for validation of functional activity of transgenic TCRs under conditions close to physiological ones, as well as for predicting their clinical efficacy are discussed. The presented approaches form the basis for rational selection of candidate receptors for their subsequent application in immunotherapy of tumors and chronic infections.