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.

Transcranial laser therapy (TLT) was tested for efficacy in a mouse model of Alzheimer's disease (AD) using a near-infrared energy laser system. TLT is thought to stimulate ATP production, increase mitochondrial activity, and help maintain neuronal function. Studies were performed to determine the effect of TLT in an amyloid-β protein precursor (AβPP) transgenic mouse model. TLT was administered 3 times/week at various doses, starting at 3 months of age, and was compared to a control group (no laser treatment). Treatment was continued for a total of six months. Animals were examined for amyloid load, inflammatory markers, brain amyloid-β (Aβ) levels, plasma Aβ levels, cerebrospinal fluid Aβ levels, soluble AβPP (sAβPP) levels, and behavioral changes. The numbers of Aβ plaques were significantly reduced in the brain with administration of TLT in a dose-dependent fashion. Administration of TLT was associated with a dose-dependent reduction in amyloid load. All TLT doses mitigated the behavioral effects seen with advanced amyloid deposition and reduce the expression of inflammatory markers in the AβPP transgenic mice. All TLT doses produced an increase in sAβPPα and a decrease in CTFβ levels consistent with inhibition of the β-secretase activity. In addition, TLT showed an increase in ATP levels, mitochondrial function, and c-fos suggesting an overall improvement in neurological function. These studies suggest that TLT is a potential candidate for treatment of AD.

In addition to its function in calcium and bone metabolism, vitamin D is neuroprotective and important for mitigating inflammation. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the central nervous system, characterized by neuronal loss in many areas of the brain, and the formation of senile (neuritic) plaques, which increase in number and size over time. The goal of this project was to investigate whether vitamin D3 supplementation would affect amyloid plaque formation in amyloid-β protein precursor (AβPP) transgenic mice that spontaneously develop amyloid plaques within 3–4 months of birth. AβPP mice were fed control, vitamin D3-deficient or vitamin D3-enriched diets for five months, starting immediately after weaning. At the end of the study, the animals were subjected to behavioral studies, sacrificed, and examined for bone changes and brain amyloid load, amyloid-β (Aβ) peptide levels, inflammatory changes, and nerve growth factor (NGF) content. The results obtained indicate that a vitamin D3-enriched diet correlates with a decrease in the number of amyloid plaques, a decrease in Aβ peptides, a decrease in inflammation, and an increase in NGF in the brains of AβPP mice. These observations suggest that a vitamin D3-enriched diet may benefit AD patients.