Therapeutisches Potenzial und Risikoanalyse von T-Zellrezeptor genmodifizierten Knochenmark-Stammzellen für die adoptive T-Zelltherapie

• Antragsteller: Professor Dr. Wolfgang Uckert
• Fachliche Zuordnung: Hämatologie, Onkologie
• Förderung: Förderung von 2006 bis 2014
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 22749242

The therapeutic efficacy of adoptively transferred cytotoxic T cells (CTLs) has been demonstrated in the treatment of leukemias and viral infections after allogeneic bone marrow transplantation. However, this approach is restricted by the difficulty to reproducibly generate sufficient amounts of specific T cells in vitro. Recent gene therapy approaches include the genetic engineering of T cells to change their antigen specificity. One example is the T cell receptor (TCR) gene transfer to achieve virus or tumor specificity. Such redirected T cells can recognize and destroy virus infected and tumor cells. Indeed, there is a growing number of studies employing TCR genemodified T cells that are used in experimental models and in first clinical trials. Most commonly, retroviral vectors are employed to genetically modify T cells, but also hematopoietic stem cells (HSCs). In a gene therapy trial, where the gene encoding the common cytokine receptor gamma chain (¿c) was transferred into HSCs, the retroviral integration induced an uncontrolled exponential clonal proliferation and led to lymphoma-like disease. Even though it is not yet clear what caused the malignancy, it is thought that the undifferentiated state as well as the growth advantage conferred by the ¿c may have contributed to lymphomatogenesis. Since the TCR confers a growth advantage as well, at least as long as its cognate ligand (MHC-peptide complex) of viral or tumor origin is present, it is indispensable to evaluate the risk of TCR gene transfer on (i) transgene level: Can genes providing a transient growth advantage (such as TCR) sustain the amplification of clones with malignant potential? (ii) Cellular level: Are terminally differentiated T cells also prone to develop malignancy? These issues will be addressed in human and mouse models.

• DFG-Verfahren: Schwerpunktprogramme
• Teilprojekt zu: SPP 1230: Mechanisms of gene vector entry and persistence