Herrlinger U, Kramm C M, Johnston K M, Louis D N, Finkelstein D, Reznikoff G, Dranoff G, Breakefield X O, Yu J S
Neurology Service, Massachusetts General Hospital East, Charlestown 02129, USA.
Cancer Gene Ther. 1997 Nov-Dec;4(6):345-52.
Brain tumors have an immunoprivileged status which contributes to their refractoriness to treatment. In this study, immune rejection of GL261 glioma tumors in the mouse brain was achieved by subcutaneous vaccination with GM-CSF-transduced glioma cells. Cultured GL261 cells were transduced to secrete murine GM-CSF using a retrovirus vector, then irradiated, and injected subcutaneously into H-2 matched C57BL/6 mice. In prevaccination studies, the median survival time (MST) of animals vaccinated with 5 x 10(4) or 5 x 10(5) GM-CSF-transduced cells 7 days prior to intracranial injection of 10(6) nontransduced, nonirradiated GL261 cells was significantly prolonged by 45-50% compared with animals vaccinated in parallel with nontransduced, irradiated glioma cells. In treatment of established gliomas, the MST of animals, which were treated subcutaneously with 5 X 10(6) irradiated GM-CSF-transduced cells 3 days after intracranial injection of 2 x 10(4) nontransduced cells, was prolonged significantly by 36% compared with animals treated with the same number of nontransduced, irradiated cells or to sham-treated animals. In prevaccination studies, histology of brain tumors 4 days after intracranial tumor cell injection revealed infiltrates of CD8+ lymphocytes and eosinophils, the latter exclusively in animals vaccinated with GM-CSF-transduced cells, Thus, subcutaneous injection of irradiated GM-CSF-transduced glioma cells can induce a potent immune response to intracranial gliomas both as a vaccination against subsequent intracranial glioma cell implantation and for treatment of established intracranial glioma.
脑肿瘤具有免疫赦免状态，这导致它们对治疗具有抗性。在本研究中，通过皮下接种经GM-CSF转导的胶质瘤细胞实现了对小鼠脑内GL261胶质瘤肿瘤的免疫排斥。使用逆转录病毒载体将培养的GL261细胞转导以分泌小鼠GM-CSF，然后进行照射，并皮下注射到H-2匹配的C57BL/6小鼠中。在接种前的研究中，在颅内注射10(6)个未转导、未照射的GL261细胞前7天接种5×10(4)或5×10(5)个经GM-CSF转导细胞的动物，其平均生存时间（MST）与平行接种未转导、照射的胶质瘤细胞的动物相比显著延长了45-50%。在治疗已形成的胶质瘤时，在颅内注射2×10(4)个未转导细胞3天后皮下注射5×10(6)个经照射的GM-CSF转导细胞的动物，其MST与接受相同数量未转导、照射细胞治疗的动物或假治疗动物相比显著延长了36%。在接种前的研究中，颅内注射肿瘤细胞4天后脑肿瘤的组织学检查显示有CD8+淋巴细胞和嗜酸性粒细胞浸润，后者仅在接种经GM-CSF转导细胞的动物中出现。因此，皮下注射经照射的GM-CSF转导的胶质瘤细胞既可以作为针对随后颅内胶质瘤细胞植入的疫苗接种，也可以用于治疗已形成的颅内胶质瘤，从而诱导对颅内胶质瘤的有效免疫反应。
