Intracerebral versus subcutaneous immunization with allogeneic fibroblasts genetically engineered to secrete interleukin-2 in the treatment of central nervous system glioma and melanoma.
OBJECTIVE
The purpose of this study was to determine the optimal route of delivery of gene therapy for an intracerebral (IC) tumor. In previous studies, treatment of an IC tumor with the IC administration of a cellular vaccine consisting of allogeneic fibroblasts genetically engineered to secrete cytokines prolonged survival. Systemic delivery of gene therapy is of significant clinical interest.


METHODS
In this study, allogeneic fibroblasts engineered to secrete interleukin (IL)-2 (LM-IL-2 cells) were administered either subcutaneously or intracerebrally to C57BL/6 mice with IC glioma. In addition, fibroblasts genetically engineered to express (antibody-defined) melanoma-associated antigens and to secrete IL-2 (RLBA-IL-2) were injected either intracerebrally or subcutaneously into mice bearing IC melanoma.


RESULTS
The results indicate a significant prolongation of survival in mice with IC glioma treated intracerebrally with LM-IL-2 cells, relative to the survival of mice with IC glioma treated subcutaneously with LM-IL-2 cells or untreated mice with glioma. The specific release of isotope from 51Cr-labeled glioma cells coincubated with spleen cells from animals treated either subcutaneously or intracerebrally with LM-IL-2 cells was significantly greater than the release of isotope from glioma cells coincubated with spleen cells from nonimmunized mice. In a similar fashion, the survival of mice with IC B16 melanoma immunized intracerebrally with RLBA-IL-2 cells was significantly longer than nonimmunized mice injected with B16 cells alone. In contrast, the survival of mice with IC melanoma treated by subcutaneous injection with RLBA-IL-2 cells was not significantly different than that of untreated mice. Using a 51Cr-release assay, the specific release of isotope from labeled B16 cells coincubated with spleen cells from mice immunized either intracerebrally or subcutaneously with RLBA-IL-2 cells was significantly higher than that of B16 cells coincubated with cells from nonimmunized mice.


CONCLUSIONS
Direct IC administration of fibroblasts genetically engineered to secrete IL-2 was more effective in prolonging survival than peripheral subcutaneous administration in the treatment of mice with IC glioma or melanoma.
Glick
R P
RP
Division of Neurosurgery, Cook County Hospital, Chicago, Illinois, USA.
Lichtor
T
T
Mogharbel
A
A
Taylor
C A
CA
Cohen
E P
EP
D000818:Animals; D000951:Antigens, Neoplasm; D001921:Brain; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy*; D005260:Female; D005347:Fibroblasts; D005818:Genetic Engineering; D015316:Genetic Therapy; D005910:Glioma / Q000276:immunology / Q000628:therapy*; D006801:Humans; D016219:Immunotherapy, Adoptive; D007267:Injections; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D058950:Melanoma-Specific Antigens; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D007376:Interleukin-2; D058950:Melanoma-Specific Antigens; D009363:Neoplasm Proteins