Combined Gene Therapy and Chemotherapy Kills Brain Tumors

Cancer researchers have developed a combined immunological and chemotherapeutic strategy for attacking and destroying glioblastoma multiforme (GBM) brain tumors. Glioblastoma multiforme is the most aggressive type of brain tumor, with only 5% of patients surviving five years following diagnosis.

Investigators at Cedars-Sinai Medical Center (Los Angeles, CA, USA) based their research on previous studies that had shown that attempts to destroy GBM tumors failed primarily because of the lack of dendritic cells within the central nervous system.

To find a way around this problem, the investigators first established a mouse model for GBM. Then, they injected viral vectors carrying the genes for Fms-like tyrosine kinase 3 ligand (Ftl3L) and for thymidine kinase (TK) into the tumor. Ftl3L is a protein that attracts dendritic cells, while TK renders cells susceptible to the anticancer drug gancyclovir.

Results published in the January 13, 2008, online edition of the journal PLoS Medicine revealed that expression of both Flt3L and TK (but not of either protein alone) plus gancyclovir treatment shrank the tumors and greatly improved the survival of the mice. This treatment strategy increased the migration of dendritic cells into the tumor provided they expressed an immune system protein called Toll-like receptor 2 (TLR2). TLR2 expression on the dendritic cells was also needed for an effective anti-tumor immune response and for tumor regression. TLR2 was responding to high-mobility-group box 1 (HMGB1), a protein released by the dying tumor cells. This finding was confirmed by showing that treatment of the tumor-bearing mice with the HMGB1 inhibitor glycyrrhizin blocked the therapeutic effect of Flt3L/TK expression.

"Toll receptors play a major role in the immune system's recognition of bacterial and viral components, but now we have shown that they also trigger an immune response against tumors,” said senior author Dr. Maria G. Castro, codirector of the Gene Therapeutics Research Institute at Cedars-Sinai Medical Center. "Activation of Toll receptors was essential for two key stages in initiating immune responses against the tumor – the migration of peripheral dendritic cells into the brain tumor and the subsequent activation of dendritic cells and stimulation of a specific antitumor cytotoxic T-cell mediated response.”

The investigators reported that other tumor cell types release HMGB1 when they are killed, and that the Flt3L/TK expression strategy can kill other tumors growing in mouse brains.

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