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Gene Therapy Approach "Trains" Immune System

Study in Laboratory Rats Supports Future Translation to Human Trial

A new gene therapy approach that attracts and "trains" immune system cells to destroy deadly brain cancer cells also provides long-term immunity, produces no significant adverse effects and -- in the process of destroying the tumor -- promotes the return of normal brain function and behavioral skills, according to a study conducted by researchers at Cedars-Sinai's Board of Governors Gene Therapeutics Research Institute.

The study was conducted in a recently developed laboratory rat model of glioblastoma multiforme (GBM) that closely simulates outcomes in humans and supports the translation of this procedure to human clinical trials later this year. Results of the study are described in the Feb. 19 issue of Molecular Therapy, the journal of the American Society for Gene Therapy.

"These findings appear to be a significant milestone in creating an effective treatment for glioblastoma multiforme," said Maria Castro, Ph.D., co-director of the Board of Governors Gene Therapeutic Research Institute and principal investigator of the study. "This therapy significantly improved survival rate, induced long-lasting systemic anti-tumor immunity, and resolved the neuropathological abnormalities caused by the tumors, which has been a stumbling block to many promising treatments."

Humans with GBM often suffer behavioral abnormalities that affect concentration, memory and balance. In the animal studies, rats exhibited abnormal rotational movements. The research team found that as the tumors grew, they displaced and compressed nerve terminals and impulse-conducting axons. But long-term survivors who had received the gene therapy did not have long-term injury or behavioral impairment resulting from the tumor or the treatment.

"Tumor growth causes behavioral deficits, but even treatments, such as chemotherapy and radiation therapy, can cause learning disabilities and other cognitive problems. In our animal study, this therapy eliminated the tumor mass and reversed the deficits that were caused by the tumor," said Pedro Lowenstein, M.D., Ph.D., co-principal investigator on the study; principal investigator in the proposed phase I clinical trial and director of the Board of Governors Gene Therapeutics Research Institute.

Glioblastoma multiforme is the most common and deadly type of brain cancer, and is extremely difficult to treat.

In the gene therapy approach developed at Cedars-Sinai, researchers used a virus stripped of its disease-causing genes as a vehicle to deliver two therapeutic proteins directly into the tumor cells. One protein, FMS like tyrosine kinase 3 ligand (Flt3L), drew dendritic cells into the brain. Another protein, herpes simplex virus type 1 thimidine kinase (HSV1-TK), combined with the antiviral gancyclovir (GCV), killed tumor cells.

"In the fairly near future, this combined gene therapy may work synergistically with current therapies, including surgery, chemotherapy and radiation therapy allowing doctors to increase long term survival while and avoiding serious side effects," Dr. Castro said. "But with the safety, effectiveness and curative potential seen in these studies, we are hopeful that gene therapy for GBM could become the new standard of care."