Brain Tumor Therapy Using Genetically Engineered Replication-Competent Virus

Publisher Summary This chapter focuses on brain tumor therapy using genetically engineered replication-competent virus. The most malignant and fastest growing tumor in the brain is glioblastoma multiforme. This tumor, even with modern technology using neurosurgical techniques, radiation, and chemotherapy, allows a patient a median survival of about one year after diagnosis. The proposed therapeutic mechanisms involve either direct cell killing by the virus or the production of new antigens on the tumor cell surface to induce immunologic rejection. Viruses are the most efficient means for getting foreign genes into cells. Various preliminary studies have suggested that the concept of viral tumor therapy is feasible because a virus can be genetically engineered to kill glioblastoma cells in situ with relative sparing of the surrounding brain. In glioblastoma multiforme, the tumor cells are rapidly proliferating, whereas the normal brain cells are quiescent and postmitotic. Therefore, the tumor cells provide a selected target for the mutated virus to replicate, lyse these cells, and spread to the surrounding proliferating tumor cells. Many steps are involved in viral antitumor therapy: distinguishing between the normal tissue and abnormal tumor cells .effective targeting and elimination of the abnormal cells by the virus and amplifying this effect to surrounding tumor cells. The discussion includes replication-incompetent and replication-competent vectors for gene transfer to tumors and the safety issues associated with it. To overcome the potential safety problems related to the viral antitumor therapy, other HSV mutants with decreased neurovirulence are also explored. Such mutant(s) would enable the administration of higher doses of virus, rendering treatment more effective, for example mutant RE6 and mutant R3616. Immune-mediated tumor therapy via gene delivery is an active area of research. Also, the viruses described in this chapter can be further engineered to produce cytokines to increase antitumor therapy.