FORGEN

RESEARCH NETWORK FOR FUNDAMENTAL GENETIC TECHNOLOGY

FORGEN II VV7 Replication deficient herpesvirus vectors with shut-off function for T lymphocytes

T lymphocytes mediate protective immunity against infectious pathogens and cancer cells. Novel clinical strategies aim in utilizing T lymphocytes for cancer therapy. Gene vectors for T cells on the basis of herpesvirus saimiri are advantageous: They do not integrate into the cellular genome and they allow the stable and efficient expression of foreign genes in human T lymphocytes. Moreover, there is no limitation in humans by preexisting immunity to this virus. Finally, specific virus genes can be used to amplify functional and antigen specific T cells in a simple and efficient way. Autologous T cells, which had been amplified using the virus vector, were well tolerated after transfusion in animals. This project aims in constructing herpesvirus vectors for the direct control of unexpected side effects. Replication deficient virus vectors shall be constructed by deleting essential regulatory functions in order to exclude virus release from the target cells. Packaging cell lines expressing the deleted viral gene will allow the amplification of otherwise replication deficient viruses. In another part of the project, a novel elimination system will be tested utilizing the cellular gene cytochrome P450 2B1 for activating cytotoxic drugs. This mechanism shall provide improved means for the targeted elimination of cells after therapeutic use or in case of unexpected side effects. Finally, conditional virus vectors carrying regulated genes for T-cell amplification shall be tested. Cell proliferation would be switched off by tetracyclines. With the help of such vectors, we aim in an improved and more secure T-cell mediated tumor therapy. This project is conducted in close collaboration with the project of Prof. Hillen.