Abstract
BackgroundGlioblastoma (GBM) is the deadliest of brain tumors. Standard treatment for GBM is surgery, followed by combined radiation therapy and chemotherapy. Current therapy prolongs survival but does not offer a cure. We report on a novel immunotherapy against GBM, tested in an animal model of C57BL/6 mice injected intra-cranially with a lethal dose of murine GL261 glioma cells.MethodsTen week-old C57BL/6 mice were anesthetized before injection of 2 × 104 GL261 cells in the right cerebral hemisphere and after 3 days half of the mice were administered a single subcutaneous (s.c.) injection of irradiated semi-allogeneic vaccine, while mock-vaccinated mice received a s.c. injection of phosphate-buffered saline (PBS). Tumor engraftment was monitored through bioluminescence imaging (BLI). Length of animal survival was measured by Kaplan–Meier graphs and statistics. At time of sacrifice brain tissue was processed for estimation of tumor size and immunohistochemical studies.ResultsOverall survival of vaccinated mice was significantly longer compared to mock-vaccinated mice. Five to ten percent of vaccinated mice survived more than 90 days following the engraftment of GL261 cells in the brain and appeared to be free of disease by BLI. Tumor volume in the brain of vaccinated mice was on average five to ten-fold smaller compared to mock-vaccinated mice. In vaccinated mice, conspicuous microglia infiltrates were observed in tumor tissue sections and activated microglia appeared to form a fence along the perimeter of the tumor cells. The results of these animal studies persuaded the Office of Orphan Products Development of the Food and Drug Administration (FDA) to grant Orphan Drug Designation for treatment of GBM with irradiated, semi-allogeneic vaccines.ConclusionsOur preclinical observations suggest that semi-allogeneic vaccines could be tested clinically on subjects with GBM, as an adjuvant to standard treatment.
Highlights
Glioblastoma (GBM) is the deadliest of brain tumors
Single-cell suspensions of glioma 261 (GL261) and RAG-neo cultures were fused using polyethylene glycol (PEG) 1450 and semi-allogeneic somatic cell hybrids were selected in Dulbecco’s modified Eagle’s medium (DMEM) + 10 % fetal bovine serum (FBS), containing 400 μg/mL G418 and hypoxan‐ thine aminopterin thymidine (HAT) supplement
HAT-resistant and neomycin-resistant cell colonies became visible after 2–3 weeks; drug-resistant cultures were expanded and tested by Fluorescence‐activated cell sorting (FACS) for expression of cell surface antigens derived from each parental cell
Summary
Glioblastoma (GBM) is the deadliest of brain tumors. Current therapy prolongs survival but does not offer a cure. Glioblastoma multiforme (GBM) is the deadliest of brain tumors and is one of a group of tumors referred to as gliomas. Classified as a Grade IV (most serious) astrocytoma, GBMs develop from the astrocytes that support nerve cells, primarily in the cerebral hemispheres, but can develop in other parts of the brain, brainstem, or spinal cord. Americans are diagnosed with GBMs. The cure rate for GBMs is grim, with current therapy prolonging survival but not offering a cure. Standard treatment for GBM is surgery, followed by combined radiation therapy and chemotherapy. After surgery, combined chemo-radiation is used to kill residual tumor cells and to delay recurrence. With standard of care therapy, the median survival of children and adults
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