New Gene Therapy Clinical Trial for Patients Newly Diagnosed with Glioma
UCSF-led study tests a platform delivering a gene that activates an FDA-approved drug, turning it into to a widely used chemotherapy agent
The UCSF Brain Tumor Center is now recruiting patients with newly diagnosed high-grade gliomas for a phase I/IIa clinical trial with DB107-RRV, a gene therapy platform designed to selectively infect tumor cells.
The virus, DB107-RRV, has been genetically engineered to deliver a gene that converts a prodrug, DB107-FC, into the chemotherapy agent 5-fluorouracil (5-FU). Since the virus only infects the rapidly dividing cancer cells, 5-FU’s anti-cancer activity is restricted to the brain tumor.
The trial is the first time researchers are evaluating this gene therapy platform in patients with newly diagnosed gliomas at the time of diagnostic surgery and after.
“Our goal is to assess the treatment’s efficacy within the context of two important prognostic biomarkers to identify which patients may derive the most benefit,” said UCSF neuro-oncologist and the trial’s principal investigator Nicholas Butowski, MD.
The first of these biomarkers is the O-6 methylguanine-DNA methyltransferase (MGMT) gene. When the MGMT gene promoter is modified by a process called methylation, the DNA damage repair enzyme the gene encodes is not produced. This makes it so that the glioma cells are unable to fix the damage to their DNA that is caused by chemotherapy and radiation therapy.
In the clinical setting, scientists have observed that patients with a glioblastoma that has a methylated MGMT gene promoter tend to have better outcomes with the chemotherapy drug temozolomide.
Individuals newly diagnosed with either grade 3 or grade 4 diffuse gliomas will be stratified based on the levels of MGMT promoter methylation present in their tumors. Since 5-FU also works by preventing the tumor cells from dividing, the investigational agents in this clinical trial could enhance the effects of radiation therapy patients will also be receiving as part of their standard of care. Patients with MGMT methylated tumors will also receive temozolomide.
In additional to MGMT promoter methylation levels, Butowski and his colleagues will also be genetically testing patients for the presence of biomarker called DGM7. The pharmaceutical company collaborating with UCSF on the trial, Denovo Biopharma, found this biomarker seems to correlate with better patient outcomes. Their analysis of a previous clinical trial with this gene therapy platform in patients with recurrent high-grade gliomas indicated that patients who were DGM7 positive lived longer than those who were DGM7 negative.
While the prodrug being used in this trial, DB107-FC, readily crosses the blood-brain barrier, the researchers are attempting to increase how much of the gene therapy reaches the tumor cells. Patients will receive an intravenous injection of the virus in addition to having it locally applied during their tumor resection surgery.
The multicenter trial is supported by an $11.8 million grant from the California Institute for Regenerative Medicine to UCSF Brain Tumor Center principal investigator Noriyuki Kasahara, PhD, whose lab is continuing to develop novel therapies against brain tumors.
For More Information on Enrollment:
DB107-RRV, DB107-FC, and Radiation Therapy with or without Temozolomide (TMZ) for High Grade Glioma