INTRACEREBRAL VERSUS SUBCUTANEOUS IMMUNIZATION WITH ALLOGENEIC FIBROBLASTS GENETICALLY-ENGINEERED TO SECRETE INTERLEUKIN-2 IN THE TREATMENTOF CENTRAL-NERVOUS-SYSTEM GLIOMA AND MELANOMA

OBJECTIVE: The purpose of this study was to determine the optimal rout e of delivery of gene therapy for an intracerebral (IC) tumor. In prev ious studies, treatment of an IC tumor with the IC administration of a cellular vaccine consisting of allogeneic fibroblasts genetically eng ineered to secrete cytokines prolonged survival. Systemic delivery of gene therapy is of significant clinical interest. METHODS: In this stu dy, allogeneic fibroblasts engineered to secrete interleukin (IL)-2 (L M-IL-2 cells) were administered either subcutaneously or intracerebral ly to C57BL/6 mice with IC glioma. In addition, fibroblasts geneticall y engineered to express (antibody-defined) melanoma-associated antigen s 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 gliom a treated intracerebrally survival in mice with IC glioma treated intr acerebrally 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 Cr-51-labeled glioma cells coincubated with spleen cells from animals treated either subcu taneously or intracerebrally with LM-IL-2 cells was significantly grea ter than the release of isotope from glioma cells coincubated with spl een cells from nonimmunized mice. In a similar fashion, the survival o f mice with IC B16 melanoma immunized intracerebrally with RLBA-IL-2 c ells was significantly longer than nonimmunized mice injected with B16 cells alone. In contrast, the survival of mice with IC melanoma treat ed by subcutaneous injection with RLBA-IL-2 cells was not significantl y different than that of untreated mice. Using a Cr-51-release assay, the specific release of isotope from labeled B16 cells coincubated wit h spleen cells from mice immunized either intracerebrally or subcutane ously with RLBA-IL-2 cells was significantly higher than that of B16 c ells coincubated with cells from nonimmunized mice. CONCLUSION: Direct IC administration of fibroblasts genetically engineered to secrete IL -2 was more effective in prolonging survival than peripheral subcutane ous administration in the treatment of mice with IC glioma or melanoma .