Eradication of established intracranial rat gliomas by transforming growth factor beta antisense gene therapy
Eradication of established intracranial rat gliomas by transforming growth factor beta antisense gene therapy
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DOI：
10.1073/pnas.93.7.2909
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发表时间：
1996-04-02
影响因子：
11.1
通讯作者：
Sobol, RE
中科院分区：
文献类型：
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作者：
Fakhrai, H;Dorigo, O;Sobol, RE
与人类胶质瘤一样，大鼠9 L胶质肉瘤分泌免疫抑制性转化生长因子β使用9 L模型，我们测试了我们的假设，即对胶质瘤细胞进行基因修饰以阻断TGF-β表达可以增强其免疫原性并使其更适合于主动肿瘤免疫治疗，用经遗传修饰以抑制TGF-β 1的9 L细胞皮下免疫荷瘤动物用反义质粒载体表达β导致存活12周的动物数量显著增加（11/11，100%），与用对照载体修饰的9 L细胞免疫相比（2/15，13%）或用白细胞介素2逆转录病毒载体转导的9 L细胞（3/10，30%）（两个比较P < 0.001），治疗后12周植入部位的组织学评价显示无残留肿瘤的证据，用淋巴结效应细胞进行的体外肿瘤细胞毒性试验显示，用TGF-β反义寡核苷酸免疫的动物的裂解活性增加了3- 4倍。与用对照载体或白介素2基因修饰的肿瘤细胞免疫相比，这些结果表明，抑制TGF-β表达显著增强了肿瘤细胞的免疫原性，并支持未来TGF-β的临床评价。TGF-β反义基因治疗表达TGF-β的肿瘤
Like human gliomas, the rat 9L gliosarcoma secretes the immunosuppressive transforming growth factor beta (TGF-beta), Using the 9L model, we tested our hypothesis that genetic modification of glioma cells to block TGF-beta 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-beta 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-beta antisense-modified tumor cells compared to immunizations with control vector or interleukin 2 gene-modified tumor cells, These results indicate that inhibition of TGF-beta expression significantly enhances tumor-cell immunogenicity and supports future clinical evaluation of TGF-beta antisense gene therapy for TGF-beta-expressing tumors.