Immune-mediated gene therapy ups survival in glioblastoma model

In a rat model of glioblastoma multiforme, treatment with a recombinant adenovirus expressing human soluble fms-like tyrosine kinase 3 ligand (hsFlt3L) stimulates the immune system to fight the tumor, resulting in significant tumor shrinkage and increased survival time.

“This is the first demonstration that hsFlt3L, a cytokine used to stimulate anti-tumor responses in tumors in other organs, may have an important role for treating intracranial brain tumors,” investigators write in the December issue of Molecular Therapy.New treatments for glioblastoma multiforme are desperately needed, Dr. Sumia Ali and colleagues from the Gene Therapeutics Research Institute at Cedars-Sinai Medical Center in Los Angeles note in their report. Despite aggressive therapy, median survival after diagnosis is only 6 to 12 months.Their rationale for testing hsFlt3L gene therapy is its “unique ability to increase the number of dendritic cells (DCs) from circulating precursors.” They hypothesized that hsFlt3L would promote infiltration and/or differentiation of DCs into the CNS and increase the capacity of the brain to promote antigen presentation.In the study, Lewis rats bearing intracranial syngeneic CNS-1 gliomas received intracranial injections of recombinant adenoviral vectors encoding hsFlt3L in escalating doses or saline placebo.According to Dr. Ali’s group, hsFlt3L injections led to a marked increase in the number of cells bearing DC markers at the site of injection, consistent with a proinflammatory and immune-stimulating effect.Moreover, hsFlt3L gene therapy improved survival in a dose-dependent manner, the team reports, with 70% of treated animals surviving for up to 6 months. Saline-treated control animals died within 30 days.Of the surviving treated animals, 33.3% were tumor-free at 3 months while the remaining 66.6% still harbored “irregular tumors growing within the striatum and the overlying neocortex,” they report.Some of the tumor-bearing animals still alive at 3 months were tumor-free by 6 months and no animals died between 3 and 6 months. This suggests that tumor growth was significantly inhibited by hsFlt3L and reflect an “ongoing battle between the tumor and the immune system,” the investigators note.”Our results have profound implications for immune-mediated brain tumor therapy,” Dr. Ali and colleagues conclude.Given both the effectiveness of hsFlt3L gene therapy in an animal model and the lack of overt adverse effects to the surrounding normal brain, “we hope to start clinical trials using this combined immune and suicide gene therapy approach within the next three years,” co-investigator Dr. Maria G. Castro said in a statement.(Source: Mol Ther 2004;10:1071-1084: Reuters Health: Oncolink: December 2004.)