Harvard-Affiliated Investigators Conduct First Study of Drug-Inducible Gene Therapy Evidencing Positive Potential

Harvard-Affiliated Investigators Conduct First Study of Drug-Inducible Gene Therapy Evidencing Positive Potential TrialsiteN

Clinical investigators from Brigham and Women’s Hospital and Dana-Farber Cancer Institute sought to test the safety and effectiveness of a way to control a powerful immunotherapy, known as interleukin-12 (hIL-12), by using an oral activator—a treatment to refine control over when a gene gets activated—in patients with recurrent glioblastoma (brain cancer).

Sponsored by Ziopharm Oncology, Inc., this new trial shows promise. Many previous trials were stopped due to unacceptable toxicity. This drug-inducible gene therapy method demonstrated anti-tumor effects with tolerable and reversible side effects. Moreover, the study establishes a baseline to build upon—paving the way for more clinical trials using this therapy with possible applicability to glioblastoma and others. The results of this study were published in Science Translational Medicine.

The Problem

Glioblastoma represents an aggressive and incurable cancer with a median overall survival of 15 months, reports MedicalXpress. Glioblastoma patients will receive surgery, radiation, and chemotherapy but nearly in every case the tumors return within months. Once it recurs, death is imminent.

The Study

In this phase I, multi-center study, 31 patients were enrolled who are experiencing recurrent glioblastoma and were given veledimex, an oral activator, prior to surgery for brain tumor removal. The patients were given an injection of hIL-12 vector which delivered an IL-12 drug at the time of surgery. The patients were given veledimex for 14 consecutive days.

The patients received 10-40 mg of veledimex and the investigators noted increases of veledimex, IL-12 and other measures of immune activity in the patients’ blood. The research team reported that the frequency and severity of adverse events including cytokine release syndrome, correlated with the veledimex dose, reversing promptly upon discontinuation. MedicalXpress reported patients taking the 20mg dose of veledimex experienced an overall survival rate of 12.7 months.

Corticosteroid Findings

Corticosteroids when administered to the glioblastoma patients on IL-12 gene therapy negatively impacted survival. These steroids are prescribed to relieve brain swelling.


Investigators studied tissue from the tumor treated with the IL-12 gene therapy and found evidence that immune cells had infiltrated the tumor—a very good sign that the approach can work. However, they also found an increase in checkpoint signaling which is a trick that cancer cells play to impede the immune system.

Next Steps

The team is now combining IL-12 gene therapy with intravenous checkpoint inhibitors and they have commenced a Phase I clinical trial.

Who is Ziopharm Oncology, Inc?

Founded in 2005, the Boston, MA-based venture employs novel gene expression and control technology to deliver DNA for the treatment of cancer. Their technology platform employs Intrexon Corporation’s RheoSwitch Therapeutic System® to turn on and off and precisely modulate gene expression at the cancer site in order to improve the therapeutic index. The technology is being evaluated in clinical trials of the immune system cytokine interleukin-12 for the treatment of breast cancer and advanced melanoma as some examples.


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Lead Research/Investigator

Dr. E. Antonio Chiocaa, MD, PhD, FAANS