Patients with malignant brain tumors have poor prognoses even when treated with the best conventional therapy of surgical resection, radiation therapy, and chemotherapy. Hence, investigation of new therapeutic approaches for these neurological diseases is needed. One novel approach has been the introduction of genes into tumor cells that render them sensitive to cytotoxic drugs. Previous experiments demonstrated a robust tumoricidal activity against experimental brain using the herpes simplex virus thymidine kinase (HSVtk) gene that converts ganciclovir (GCV) to a form that is cytotoxic to rapidly dividing cells. The treatment was not as effective when tested with tumors generated from cell lines with lesser immunogenicity. These observations suggest that the tumoricidal activity results from two processes: (1) direct tumoricidal activity of HSV-tk conversion of GCV and (2) cellular immune responses. The applicant will test the hypothesis that cell death from HSV-tk/GCV treatment causes antigen presenting cells (APCS) to activate cytotoxic T lymphocyte (CTL) precursors which then destroy residual tumor and prohibit further cell growth. The presence of an immunological component can explain the weaker tumoricidal activity observed in models in which the hosts were immunoincompetent or in which the cell lines were less immunogenic. If this hypothesis is correct then (1) depending on their immunogenicity, different tumor cell lines will elicit different immune responses to HSV-tk/GCV-mediated cell death in vivo as measured by immunological analyses, and (2) neuroimmune modulation by cytokine gene transfer will elicit a heightened CTL response to the tumor cells. The objective of this project is to delineate the neuroimmunological mechanisms of cell death in experimental brain tumors following initial killing by HSV-tk/GCV treatment.
The Specific Aims are to: (1) characterize the immunological response to HSV-tk/GCV-mediated death of syngeneic experimental tumors generated by 3 glial tumor cell lines with different degrees of immunogenic potential, (2) measure the tumoricidal effects of in situ immune modulation by adenovirus-mediated transduction of tumors with the genes for the cytokines IL-2, GM-CSF, TNFA. and IL-12 with and without HSV-tk/GCV treatment. and (3) characterize the immunological responses elicited by adenoviral-mediated cytokine immune modulation with and without HSV-tk/GCV treatment.
