GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR AND B7-2 COMBINATIONIMMUNOGENE THERAPY IN AN ALLOGENEIC HU-PBL-SCID BEIGE MOUSE-HUMAN GLIOBLASTOMA-MULTIFORME MODEL/

Glioblastoma multiforme is the most common primary central nervous sys tem neoplasm, Its dismal prognosis has led to investigation of new tre atment strategies such as immunogene therapy, We transduced the human glioblastoma cell line D54MG in vitro with genes encoding the proinfla mmatory cytokine granulocyte-macrophage colony-stimulating factor (GM- CSF), the T cell co-stimulatory molecule B7-2, or both (in a bicistron ic vector) via retroviral vectors, Therapeutic gene expression by D54M G was high after transduction and selection (30 ng/10(6) cells/day for GM-CSF and >2 orders of magnitude fluorescence shift on now cytometry for B7-2), The effect of GM-CSF and/or B7-2 transducion on D54MG tumo r growth in vivo was monitored in a novel allogeneic human peripheral blood lymphocyte-severe combined inmunodeficiency mouse (Hu-PBL-SCID) model, GM-CSF- or B7-2-transduced tumors showed growth suppression in hu-PBL-reconstituted mice compared to untransduced and/or unreconstitu ted controls, Growth suppression was greatest for B7-2, Furthermore, v accination with irradiated GM-CSF/B7-2-transduced tumor cells markedly inhibited growth of wild-type tumors at distant sites, Thus, this stu dy illustrates a potential gene therapy strategy for glioblastoma mult iforme patients using GM-CSF and/or B7-2 transduced tumor vaccines, Al though extension of these allogeneic studies to an autologous system i s critical, this is the first demonstration of in vivo efficacy of com bination GM-CSF and B7-2 immunogene therapy for human glioblastoma mul tiforme.