Effective cytokine gene therapy against an intracranial glioma using a retrovirally transduced IL-4 plus HSVtk tumor vaccine

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.

Sequential delivery of interferon-α gene and DCs to intracranial gliomas promotes an effective antitumor response

“…In addition, the combination of this approach with peripheral vaccine strategies may further enhance therapeutic efficacy by promoting the activity and survival of immune effector cells, which are primarily induced in the periphery. [51][52][53] Materials and methods…”

Expression of glioma-associated antigens in pediatric brain stem and non-brain stem gliomas

“…In recent years, we have examined the applicability of a series of tumor cellbased immunization approaches for patients with gliomas [9][10][11][12][13][14][15]. Although promising results have been achieved [9,16,17], a limitation of this strategy is the need for autologous tumor and the time delay involved in generating a patient-specific vaccine.…”

Characterization and transduction of a retroviral vector encoding human interleukin-4 and herpes simplex virus-thymidine kinase for glioma tumor vaccine therapy

“…4 -6 In particular, we have demonstrated, using the rat 9L gliosarcoma model, that interleukin-4 (IL-4)-transduced tumor administration induces potent protective and therapeutic immune responses against CNS tumors. 7 The efficacy of locally produced IL-4 from genetically engineered tumor cells to induce potent antitumoral immunity has also been demonstrated by other investigators in protective 8,9 and therapeutic 10,11 non-CNS animal models. IL-4, in combination with granulocyte-macrophage colony-stimulating factor, also promotes the acquisition of a dendritic cell (DC) phenotype and function in mouse bone marrow 12 and human cord blood CD34 ϩ cell 13 cultures.…”