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CSMC researchers use gene therapy to eradicate brain tumors

Researchers at Cedars-Sinai have identified a series of molecular events that harness the power of the immune system to eradicate glioblastoma multiforme brain tumors.

Their findings, based on laboratory and animal studies, appeared in the Jan. 13 issue of PLoS Medicine, an open-access online journal of the Public Library of Science.

The team is led by Maria G. Castro, Ph.D., and Pedro Lowenstein, M.D., Ph.D., co-directors of Cedars-Sinai's Board of Governors Gene Therapeutics Research Institute.

They discovered that a protein, HMGB1, released from dying tumor cells activates key immune cells called dendritic cells and stimulates a strong and effective anti-tumor immune response. The protein does so by binding to an inflammatory receptor called toll-like receptor 2, or TLR2, found on the surface of dendritic cells.

"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 Dr. Castro, one of the article¿s senior authors.

Building on 10 years of research, the scientists used a combined gene therapeutic approach, using one protein to draw dendritic cells from bone marrow into the brain tumors, and a second protein combined with the antiviral gancyclovir to kill tumor cells and elicit long-term survival.

As reported in the article, they uncovered a mechanism by which tumor cell death in response to the treatment leads to the release of the endogenous tumor protein, HMGB1, which is essential to trigger the anti-tumor immunological cascade. The study showed for the first time that HMGB1 released from dying brain cancer cells activates TLR2 signaling on tumor infiltrating dendritic cells, resulting in the activation and expansion of tumor-antigen specific T cells.

The result was the regression of brain tumors and increased survival time by six months in experimental brain tumor models.

"The discovery of a central role for HMGB1 and TLR2 in overcoming immune ignorance to the brain tumor antigens provides a new therapeutic approach in the fight against brain tumors," said Dr. Lowenstein, co-senior author. "Our conclusions relating to anti-glioma responses have also been extended to enhancing immune responses against a number of other metastatic brain cancers, such as melanoma."

He stated that plans are underway to test this therapeutic approach in a human clinical trial for recurrent brain tumors.