No abstract

To explore the potential for molecular immunotherapies in rejected the same challenge with wild-type 9L. More the treatment of malignant gliomas, we evaluated the effiimportantly, treatment of established (day 3) intracranial 9L cacy of subcutaneous tumor cell vaccines in the treatment tumors with genetically engineered tumor cells resulted in of intracranial 9L tumors, using 9L gliosarcoma cell lines long-term survival (Ͼ100 days) for 25-43% of 9L-IL4-Tk stably transduced with the murine interleukin-4 cDNA (9L-immunized animals and for 27% of nonirradiated 9L-IL4 IL4), the herpes simplex virus-thymidine kinase cDNA (9L-immunized animals. In striking contrast, no 9L-Tk, 9L-neo Tk) or both (9L-IL4-Tk). The expression of multiple genes or irradiated 9L-IL4 immunized animals survived for more from a single transcript was achieved by incorporating than 33 days. As a marker of a cellular immune response, internal ribosomal entry site (IRES) cassettes in the retrovisplenocytes from nonirradiated 9L-IL4, 9L-Tk or 9L-IL4-Tk ral constructs. Subcutaneous immunization of rats with immunized animals produced interferon-gamma (IFN-␥) in nonirradiated 9L-IL4 cells or 9L-IL4-Tk cells followed by greater amounts than those from 9L-neo immunized or treatment with ganciclovir (GCV) completely protected the Hank's balanced salts solution (HBSS) treated animals animals from a subsequent intracranial challenge with wildwhen stimulated with wild-type 9L in vitro. Our findings suptype 9L cells. In contrast, only 50% of animals immunized port the use of tumor cell vaccines expressing the IL-4 and with 9L-Tk cells and 0% of 9L-neo immunized animalsHSVtk genes for the treatment of malignant gliomas.

To provide a means for comparing strategies for cytokine gene therapy against intracranial (i.c.) tumors, we generated rat gliosarcoma 9L cells transfected with interleukin-4 (9L-IL4), interleukin-12 (9L-IL12), granulocyte-macrophage colony-stimulating factor (9L-GMCSF) or interferon-␣ (9L-IFN␣). To simulate direct and highly efficient cytokine gene delivery, cytokine transfected 9L tumors were implanted i.c. into syngeneic rats. i.c. injection led to tumor-outgrowth in the brain and killed most animals, whereas these cell lines were rejected following intradermal (i.d.) injection. Cytokineexpressing i.c. 9L tumors, however, had a greater degree of infiltration by immune cells compared with control, mocktransfected 9L-neo, but to a lesser degree than i.d. cytokine-