Eradication of Established Intracranial Rat Gliomas by Transforming Growth Factor β Antisense Gene Therapy

Like human gliomas, the rat 9L gliosarcoma secretes the immunosuppressive transforming growth factor β (TGF-β ). Using the 9L model, we tested our hypothesis that genetic modification of glioma cells to block TGF-β expression may enhance their immunogenicity and make them more suitable for active tumor immunotherapy. Subcutaneous immunizations of tumor-bearing animals with 9L cells genetically modified to inhibit TGF-β expression with an antisense plasmid vector resulted in a significantly higher number of animals surviving for 12 weeks (11/11, 100%) compared to immunizations with control vector-modified 9L cells (2/15, 13%) or 9L cells transduced with an interleukin 2 retroviral vector (3/10, 30%) (P < 0.001 for both comparisons). Histologic evaluation of implantation sites 12 weeks after treatment revealed no evidence of residual tumor. In vitro tumor cytotoxicity assays with lymph node effector cells revealed a 3- to 4-fold increase in lytic activity for the animals immunized with TGF-β antisense-modified tumor cells compared to immunizations with control vector or interleukin 2 gene-modified tumor cells. These results indicate that inhibition of TGF-β expression significantly enhances tumor-cell immunogenicity and supports future clinical evaluation of TGF-β antisense gene therapy for TGF-β -expressing tumors.