The efficacy of CD19-directed chimeric antigen receptor (CAR-)T-cell therapy in different hematologic malignancies has put cell therapy as a novel treatment option on the map. While response rates are high, relapses due to antigen escape mutants or antigen downregulation and exhaustion of T-cells occur. In addition, finding optimal target antigens, especially for solid tumours has been proven difficult. In this project, we aim to optimize the efficacy of in-house developed CD70-directed T -cell therapy. CD70 was selected as a target antigen because it is expressed in a wide range of human malignancies, while it is largely absent in healthy tissues. We will attempt to transform the endogenous TCR into an HLA-independent TCR-like receptor using CRISPR/Cas9-mediated homology directed repair.  The edited T-cells will be evaluated using in vitro and in vivo functional assays. Eventually, the best construct will be used in PDX models as a bridge to clinic. Since CD70 is also expressed on activated T-, B- and dendritic cells , possible autoreactivity needs to be assessed. For this, we will use HIS mice and assess their immunologic functionality after CD70-directed T-cell therapy.