A novel immune-based, gene therapy approach is entering phase 2 trials (ClinicalTrials.gov Identifier: NCT04006119) for glioblastoma multiforme (GBM) after promising preliminary safety and efficacy data. Despite encouraging results in several tumor types such as melanoma, colorectal, and lung, immunotherapies have yet to show any significant benefit in patients with brain tumors. The new technique by Ziopharm hopes to reverse that trend.
“The brain is built to not be touched by our own immune system; it’s encased in the dura and the blood brain barrier,” said Katy Peters, MD, PhD, neuro-oncologist at the Preston Robert Tisch Brain Tumor Center and associate professor of neurosurgery at Duke University Medical Center, Durham, North Carolina. “In glioblastoma patients, white blood cells at diagnosis are sequestered in the bone marrow. This is our biggest hurdle — the immune cells are essentially unable to reach the tumor,” added Dr Peters.
There has been some recent evidence1,2 showing that immunotherapy treatment for melanoma or lung cancers can actually boost the immune response against metastatic disease in the central nervous system, but a general consensus remains that GBMs are fraught with an immunosuppressive environment.
“[There are] several chemicals produced by GBM that make an immunosuppressive environment in general,” said Vyshak Venur, MD, medical oncologist at the Seattle Cancer Care Alliance and assistant professor at the University of Washington School of Medicine. “Glioblastoma also has a low mutational burden — unlike melanomas and lung cancers — which compounds this low response to immunotherapy,” he added.
GBM typically has a low tumor mutation burden and is considered immunologically “cold.” Several studies with PD-1 inhibitors, both alone, and in combination with drugs such as bevacizumab, have shown no significant benefit in patients. The Ziopharm approach uses an adenovirus vector encoding IL-12 — injected directly into the tumor — in an attempt to boost immune recognition of the tumor.
“IL-12 can really be thought of as a master regulator of the immune system — it’s this molecule that [the] immune system uses as an alarm bell. If you have an infection, the way that you recruit your immune system to a point of danger is via IL-12,” said Laurence Cooper, MD, PhD, CEO at Ziopharm.
Crucially, in contrast to most other gene-therapy approaches that use a viral vector, the production of IL-12 can then be “switched on” by the patient taking the small-molecule drug veledimex orally.
“This virus unpacks the IL-12 molecule, but it delivers it under the control of the switch of a drug, so we can control the amount. If the immune response becomes too much, for example triggering a cytokine release syndrome (CRS), we can back off,” said Dr Cooper.
Researchers have been trying for years to utilize immunotherapy approaches against brain tumors with little success so far — so how unique is the Ziopharm approach?
“It is very innovative; what’s unique about this approach is that it is 2-pronged, where they are delivering the IL-12 to the tumor cavity itself and then using this activator of the IL-12 to control it,” said Dr Peters.