Optimisation of CD70-targeted adoptive cell therapy

01 November 2023 → 31 October 2027
Research Foundation - Flanders (FWO)
Research disciplines
  • Medical and health sciences
    • Biopharmaceuticals
    • Hematology
    • Adaptive immunology
    • Applied immunology
    • Cancer therapy
Nanobodies CRISPR guided gene editing Adoptive cell therapy
Project description

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. Basically, a CD70-directed nanobody will be fused to the endogenous TCR. We will call this construct a nanoTCR. For this construct, several variable TCR domains will be tested. The edited T-cells will be evaluated using in vitro and in vivo functional assays. Eventually, the best nanoTCR 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.