Recombinant retroviruses (RV) have been widely used as vectors for clinical gene therapy of malignant @entity1313 . Because of the very limited stability of these vectors in @entity1358 ( @entity1358 ) are routinely used for intratumoral RV release. The host immune system, however, recognizes the intratumorally grafted allogeneic or xenogeneic @entity1358 , and mounts an immune response against them. Humoral and cellular immune responses eventually result in @entity4085 and in limited success of RV mediated gene therapy approaches. This study presents a non-pharmacological and spatially limited approach for protection of @entity1358 grafted in the CNS against destruction by host immune responses. @entity19 fibroblast-derived @entity1358 expressing @entity778 thymidine kinase (HSV-tk) were genetically modified to co-express a @entity1 @entity12 ( @entity12 ) deletion mutant (DeltaFasL) resistant to enzymatic cleavage and shedding. Direct interactions between Fas ( @entity1197 ) on lymphocytes and DeltaFasL on @entity1358 upon cell-cell contact rapidly caused apoptosis in lymphocytes. In addition, cultured @entity1313 cells (U87, LN18, LN229) transduced with DeltaFasL-RV were rendered apoptotic by Fas/DeltaFasL interaction. DeltaFasL-expressing @entity1358 grafted in a 9L @entity35 @entity1313 model survived in significantly higher numbers compared with control @entity1358 , and did not cause an increase in neutrophil infiltration of @entity5 . Gene therapy of @entity5 bearing animals grafted with the modified DeltaFasL- @entity1358 and given the prodrug Ganciclovir resulted in significantly increased survival rates compared to treatment with control @entity1358 and Ganciclovir. In conclusion, prolonged intratumoral presence of DeltaFasL- @entity1358 seems to be a direct consequence of the expression of the membrane-bound mutant @entity12 , and may result in increased total RV output and improved @entity5 transduction with RV.

Expression of mutant non-cleavable XXXX on retrovirus packaging cells causes apoptosis of immunocompetent cells and improves prodrug activation gene therapy in a malignant glioma model.

@entity1 :: ('9606', 'Species') :: ['human'] @entity778 :: ('MESH:D015658', 'Disease') :: ['herpes-simplex-virus type I'] @entity1313 :: ('MESH:D001932', 'Disease') :: ['brain tumor', 'malignant brain tumor', 'brain tumors'] @entity19 :: ('10090', 'Species') :: ['Murine'] @entity1197 :: ('355', 'Gene') :: ['CD95'] @entity5 :: ('MESH:D009369', 'Disease') :: ['tumor', 'tumors'] @entity4085 :: ('MESH:D009081', 'Disease') :: ['reduction of VPC numbers'] @entity1358 :: ('MESH:D002292', 'Disease') :: ['vivo, RV producing cells', 'VPC'] @entity12 :: ('356', 'Gene') :: ['Fas ligand', 'CD95L', 'FasL'] @entity35 :: ('10116', 'Species') :: ['rat']
@entity12 :: (356,Gene) :: ['Fas ligand']
