Kurzfassung

Less differentiated T cells expressing a ’stem-cell’ memory (TSCM) and central memory (TCM) phenotype have been shown to exert superior proliferative and homeostatic properties as compared to memory effector and terminally differentiated effector T cells. Moreover, there is accumulating experimental and clinical evidence that TSCM/CM can induce potent immune responses to leukemia and solid cancer. In this project we therefore explore the ex vivo generation of TSCM/CM from purified naive...Less differentiated T cells expressing a ’stem-cell’ memory (TSCM) and central memory (TCM) phenotype have been shown to exert superior proliferative and homeostatic properties as compared to memory effector and terminally differentiated effector T cells. Moreover, there is accumulating experimental and clinical evidence that TSCM/CM can induce potent immune responses to leukemia and solid cancer. In this project we therefore explore the ex vivo generation of TSCM/CM from purified naive CD45RA+ precursors by pharmacologically targeting the two major T cell differentiation signaling pathways, Wnt- and Akt/PI3K. Upon redirection by retroviral gene transfer of CD19 CAR as a proof of concept these TSCM/CM  will then be tested in vitro and in vivo for their functionality and therapeutic antitumor efficacy using CD19 expressing pre B-ALL lines or autologous EBV- transformed B cells xenografted into NSG mice prior to adoptive cellular therapy. These preclinical data should provide the basis for further translational studies.
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