Scientists have developed a '2-pronged gene therapeutic approach' that will enable tumour regression while also ensuring long-term survival of the patient. The new procedure, developed following laboratory and animal studies, is done via selective recruitment of immune cells.
Researchers at Cedars-Sinai Medical Center have identified a sequence of molecular events that could help them recruit key immune cells called dendritic cells into areas of the brain where they are not naturally found and recognize tumor cells as targets for attack.
The researchers found that a protein - HMGB1 - released from dying tumor cells activates dendritic cells and stimulates a strong and effective anti-tumor immune response.
HMGB1 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 Maria G. Castro, Ph.D., co-director of Cedars-Sinai's Board of Governors Gene Therapeutics Research Institute and one of the article's senior authors.
He added: "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 anti-tumor cytotoxic T-cell mediated response."
For the study, the researchers used a combined gene therapeutic approach, using one protein (Flt3L) to draw dendritic cells from bone marrow into the brain tumors, and a second protein (Herpes Symplex type I Thymidine Kinase, or TK), combined with the antiviral gancyclovir to kill tumor cells and elicit long-term survival.
They found a novel mechanism by which tumor cell death in response to the treatment leads to the release of an endogenous tumor protein, HMGB1, which is essential to trigger the anti-tumor immunological cascade.
For the first time, the study showed that HMGB1 released from dying brain cancer cells activates TLR2 signaling on tumor infiltrating dendritic cells, leading to the activation and expansion of tumor-antigen specific T cells.
This caused the regression of the 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 brain tumor antigens provides a new therapeutic approach in the fight against brain tumors. Our conclusions relating to anti-glioma immune responses have also been extended to enhancing immune responses against a number of other metastatic brain cancers, such as melanoma,' said Pedro Lowenstein, M.D., Ph.D., director of the Board of Governors Gene Therapeutics Research Institute and co-senior author.
The researchers are now planning to test this novel therapeutic approach in a human clinical trial for recurrent brain tumours in 2009.
The study will be published in the latest issue of PLoS Medicine, an open-access online journal of the Public Library of Science.