Synergy of gene-mediated immunoprophylaxis and microbeam radiation therapy for advanced intracerebral rat 9L gliosarcomas.
OBJECTIVE
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 implanted ic with 10(4)9LGS cells on d0. By d14, the cells had generated approximately approximately 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, approximately approximately 11 mm-high array of 20-39 microm-wide, nearly parallel beams of synchrotron wiggler-generated radiation (mainly approximately 50-150 keV X-rays) that delivered 625 Gy peak skin doses at approximately approximately 211 microm ctc intervals in approximately approximately 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, approximately approximately 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.


CONCLUSIONS
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.
Smilowitz
H M
HM
Department of Pharmacology, UCHC, Farmington, CT, USA.
Blattmann
H
H
Bräuer-Krisch
E
E
Bravin
A
A
Di Michiel
M
M
Gebbers
J-O
JO
Hanson
A L
AL
Lyubimova
N
N
Slatkin
D N
DN
Stepanek
J
J
Laissue
J A
JA
D000367:Age Factors; D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology / Q000601:surgery / Q000628:therapy*; D003131:Combined Modality Therapy / Q000379:methods; D015316:Genetic Therapy; D018316:Gliosarcoma / Q000276:immunology / Q000601:surgery / Q000628:therapy*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D007114:Immunization; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D016634:Radiosurgery / Q000379:methods*; D011879:Radiotherapy Dosage; D051381:Rats; D011916:Rats, Inbred F344; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D014162:Transfection
D016178:Granulocyte-Macrophage Colony-Stimulating Factor