Designing T-cells with desired T-cell receptor make-up for immunotherapy

Abstract

TCR gene transfer is a strategy that enables the rapid engineering of anti-leukemic T-cells with defined specificity, resulting in a so called __off the shelf __ therapy. An elegant strategy to promote persistence of TCR modified T-cells may be TCR gene transfer into CMV- and EBV-specific T-cells, which exhibit proper memory and effector phenotypes. Furthermore, these virus-specific T-cells do not induce GvHD after HLA identical allo-SCT, and thus can be safely administered. For efficient anti-leukemic reactivity of the introduced TCR coinciding with enhanced in vivo survival, a balance between cell surface expression of the introduced and endogenous TCR is required. The aim of this thesis was to optimize the efficacy of TCR gene transfer, study possibilities and restrictions of virus-specific T-cells as host cells for TCR gene transfer and characterize the occurrence of potentially harmful mixed TCR dimers and strategies to prevent their formation.