Glioblastoma treatment produces positive results

BOSTON—ZIOPHARM Oncology has announced positive results from a preclinical study of a treatment for glioblastoma, an aggressive form of brain cancer, with the biotechnology firm reporting that the administration of a DNA-based therapy dramatically slowed rates of tumor growth and increased survival in mice with brain tumors. ZIOPHARM presented its findings at the annual meeting of the American Association for Cancer Research in early April.

ZIOPHARM CEO Dr. Jonathan Lewis tells DDNews that the limitations of current treatments for glioblastoma make the findings of his company’s research particularly important. The difficulty of treating glioblastoma in humans, and its high degree of malignancy, have led to particularly low survival rates. Adults with aggressive glioblastoma face a median two-year survival rate of about 30 percent. “There has been very little movement in terms of improving survival despite many attempts to develop effective treatments,” Lewis says. “If this proves effective in humans, it has great potential to lead to a commercial application to treat people with this disease and improve survival.”

The positive findings of the preclinical study open the door to Phase 1 research of the use of ZIOPHARM’s therapy, Ad-RTS-mIL-12, as a glioblastoma treatment. The therapy is already undergoing Phase 2 research as a treatment for two other forms of cancer. “We have already shown this system can be used safely in both nonclinical and clinical studies on melanoma and breast cancer,” says Lewis.

Ad-RTS-mIL-12 is a therapy designed to enable the controlled delivery of Interleukin-12 (IL-12), a protein that plays an important role in stimulating T-cell immune response. Although IL-12 has shown to have significant antitumor effects, difficulty limiting the effects of its potentially severe toxicity has held back its clinical use. ZIOPHARM’s therapy is designed to minimize toxicity by enabling the controlled expression of IL-12 at the site of a tumor.

ZIOPHARM’s study involved injecting Ad-RTS-mIL-12 directly into tumors in mice in addition to orally administering the activator ligand veledimex. One of the main goals of the study was to examine how veledimex crosses the blood brain barrier. Another primary goal was to compare the treatment’s dose-related effects of the treatment on survival, as compared to other cancer treatments.

ZIOPHARM partnered on the study with Intrexon, a Germantown, Md.-based company specializing in synthetic biology products. ZIOPHARM used Intrexon’s RheoSwitch Therapeutic System, which gave them the ability to precisely modulate gene expression in order to control production of IL-12. “Working with Intrexon enables us to apply tools of synthetic biology in many different ways to the treatment of cancer,” says Lewis.

The study’s data showed that veledimex effectively crossed the blood brain barrier in test subjects with dose-related increases in plasma and brain tissue exposure. No accumulation in brain tissue was found following repeat dosing. ZIOPHARM also found that administering Ad-RTS-mIL-12 and veledimex resulted in four- to fivefold increases in dose-related survival. The improvements in survival occurred without increasing the treatment’s safety profile as compared to other cancer treatments, including temozolomide, bevacizumab and dexamethasone.

“We have now demonstrated in multiple preclinical studies that Ad-RTS-mIL-12 enables localized, controlled delivery of IL-12 in the brain and can produce a dose-dependent reduction in tumor growth with prolonged survival,” according to Dr. Francois Lebel, senior vice president, clinical development and medical operations at ZIOPHARM. “We are very excited to start the clinical translation of Ad-RTS-IL-12 in glioblastoma.”

Lewis says he expects Phase 1 research of the therapy to begin within the next few months, noting, “It’s possible we could have data by the end of the year regarding whether this will work in people, and by middle of next year we should have a very clear sense of its effectiveness.”