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... Show moreTCR 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. Show less
For the successful application of immunotherapy for leukemia significant numbers of viable T cells with the right antigen specificity have to be available within a limited period of time. TCR gene... Show moreFor the successful application of immunotherapy for leukemia significant numbers of viable T cells with the right antigen specificity have to be available within a limited period of time. TCR gene transfer is a promising strategy enabling the generation of large numbers of T cells with a selective antigen specificity, while reducing the time required for in vitro culture. Future clinical application of TCR engineered T cells may result in an off-the-shelf therapy with TCRs suitable for large numbers of patients. Acquisition of more insight into the possibilities and restrictions of TCR gene transfer and assessment of the efficacy of the therapeutic cells may provide a solid basis for clinical application in the near future. However, the application of immunotherapy for hematological malignancies is currently limited by the restricted number of hematopoiesis specific mHags that can be used as target antigens. Furthermore, an important issue for clinical implementation of TCR gene therapy is the prevention of the formation of mixed TCR dimers, which have recently been shown to induce autoreactivity. In addition, the future development of TCR gene therapy strategies will benefit from increased knowledge about both the T cells that serve as host cell for TCR gene transfer and other T cells present in the patient that may manipulate the immunotherapeutic responses of the TCR engineered T cells. Unfortunately, function analysis of T cell populations using biologically relevant antigens is hampered by the large number of different T cell specificities present and the difficulty to identify the specificity of T cells. The aim of this thesis was to characterize novel T cell populations that may serve as host cells for TCR gene transfer and to determine their possibilities and restrictions as TCR engineered immunotherapeutic effector cells for the treatment of hematological malignancies. Show less
