THE ROLE OF IMMUNOSUPPRESSION IN THE EFFICACY OF CANCER GENE-THERAPY USING ADENOVIRUS TRANSFER OF THE HERPES-SIMPLEX THYMIDINE KINASE GENE

Objective To determine whether the immune system limits or improves th e therapeutic efficacy of an adenovirus vector expressing the herpes s implex thymidine kinase (HSVtk) gene in a subcutaneous tumor model. Ba ckground Data Enhanced immune reactions against tumors may be therapeu tically useful. However, recent studies with adenoviral vectors show t hat immune responses limit the efficacy and persistence of gene expres sion. The effect of the immune response on cancer gene therapy with HS Vtk gene delivery by an adenovirus vector followed by treatment with g anciclovir is unclear. Methods After adenoviral transduction of a Fisc her rat syngeneic mesothelioma cell line with the HSVtk gene in vitro, subcutaneous flank tumors were established. The ability of the HSVtk/ ganciclovir system to inhibit tumor growth was compared among normal F ischer rats, immunodeficient nude rats, and Fischer rats immunosuppres sed with cyclosporin. Results HSVtk/ganciclovir therapy was more effec tive in nude rats and immunosuppressed Fischer rats than in immunocomp etent Fischer rats. Conclusion These results indicate that the immune response against adenovirally transduced cells limits the efficacy of the HSVtk/ganciclovir system and that immunosuppression appears to be a useful adjunct. These findings have important implications for clini cal trials using currently available adenovirus vectors as well as for future vector design.