Synergy of gene-mediated immunoprophylaxis and microbeam radiation therapy for advanced intracerebral rat 9L gliosarcomas

Purpose: Microbeam radiation therapy (MRT), a novel experimental radiosurgery that largely spares the developing CNS and other normal tissues, is tolerated well by developing animals and palliates advanced 9LGS tumors. This report, to our knowledge, is the first demonstration that gene-mediated immunotherapy (GMIMPR) enhances the efficacy of MRT for advanced 9LGS tumors. Methods: Seventy-six male Fischer 344 rats were implantedic with 104 9LGS cells on d0. By d14, the cells had generated ∼40 mm3 ic 9LGS tumours, experimental models for therapy of moderately aggressive human malignant astrocytomas. Each of the 14 untreated (control) rats died from a large (> 100 mg) ic tumor before d29 (median, d21). On d14, the remaining 62 rats were given deliberately suboptimal microbeam radiation therapy (MRT) by a single lateral exposure of the tumor-bearing zone of the head to a 10.1 mm-wide, ∼11 mm-high array of 20-39 μm-wide, nearly parallel beams of synchrotron wiggler-generated radiation (mainly ≈ 50-150 keV X-rays) that delivered 625 Gy peak skin doses at ∼211 μm ctc intervals in ∼300 ms either without additional treatments (MRT-only, 25 rats), with post-MRT GMIMPR (MRT + GMIMPR, 23 rats: multiple sc injections of irradiated (clonogenically-disabled) GM-CSF gene-transfected 9LGS cells), or with post-MRT IMPR (MRT + IMPR, 14 rats: multiple sc injections of irradiated (clonogenically-disabled) 9LGS cells. Results: The median post-implantation survivals of rats in the MRT-only, MRT + GMIMPR and MRT + IMPR groups were over twice that of controls; further, ∼20% of rats in MRT-only and MRT + IMPR groups survived > 1 yr with no obvious disabilities. Moreover, over 40% of MRT + GMIMPR rats survived > 1 yr with no obvious disabilities, a significant (P < 0.04) increase over the MRT-only and MRT + IMPR groups. Significance: These data suggest that the combination of MRT + GMIMPR might be better than MRT only for unifocal CNS tumors, particularly in infants and young children.