Treating glioblastoma with a Ziopharm drug and IL-12 gene therapy

Human interleukin-12 (hIL-12) is a powerful immunotherapy that can rally the immune system to attack cancer cells. But it can work too well, causing toxic inflammatory responses in ways that hinder its clinical usefulness. Ziopharm Oncology designed a control system that can switch on IL-12 gene therapy on demand. The combo approach has shown early promise in a small number of glioblastoma patients.

Investigators from Brigham and Women’s Hospital and Dana-Farber Cancer Institute found that combining Ziopharm’s small-molecule oral drug veledimex with an IL-12 gene therapy was safe in an ongoing phase 1 study of 31 patients with recurrent glioblastoma.

Although the trial was not powered to show efficacy, the researchers did find signs of positive responses, which they believe lay the groundwork for future testing of the therapy for brain cancer and beyond.

In the phase 1 trial, patients first received one dose of veledimex prior to undergoing surgery. But because the tumors had grown into the normal brain tissue, it was impossible to completely remove them. During the surgery, adenovirus vectors that carry the IL-12 gene (Ad-RTS-hIL-12) were injected directly into the tumors. The patients then took veledimex, which turned on IL-12 production—a signal for T cells to attack and destroy cancerous tissue.

Because different dosage levels of veledimex can trigger IL-12 expression at varying degrees, the researchers believe it will be possible to control its production or turn it off altogether to achieve a better safety profile According to results published in the journal Science Translational Medicine, they observed that veledimex, IL-12 and immune activity in the blood of patients correlated with the dosage strength of the drug.

The team determined that 20 mg of veledimex would be the optimal dose for further development, as more patients on the 30-mg and 40-mg doses had to stop treatment due to serious adverse events such as cytokine release syndrome. Despite that, the side effects were easily reversed after veledimex was discontinued, they reported.

The researchers saw some hints of efficacy, they said. For patients taking the 20-mg dose, median overall survival reached 12.7 months, compared to 8.14 months in historical controls. What’s more, a subset of patients who were on that dose plus minimal amounts of the corticosteroid dexamethasone had a median overall survival of 17.8 months, versus 6.4 months for others. Corticosteroids are usually prescribed to relieve brain swelling but are also immunosuppressive, potentially dampening the effectiveness of the IL-12 therapy.

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Ziopharm previously hit a manufacturing snag with the IL-12 gene therapy and put a planned phase 3 trial on hold indefinitely. But it has been able to run a phase 1 extension study that investigates the 20-mg dose of veledimex in patients. And the approach recently won an FDA “fast track” designation for recurrent glioblastoma.

Glioblastoma remains a tough-to-treat disease that has experienced many disappointments, but new ideas for treating the cancer continue to be floated. The Ivy Brain Tumor Center, for example, is pairing Karyopharm Therapeutics’ recently-approved Xpovio, a first-in-class selective inhibitor of nuclear export, with other drugs to fight glioblastoma. And scientists at the University of California, San Francisco, suggested that the GABP protein could be a potential drug target in glioblastoma as it drives mutations in TERT, which gives cancer cells the ability to divide and spread indefinitely.

In the new gene therapy trial, researchers saw evidence of increased expression of PD-1 checkpoint signaling, a mechanism cancer cells use to evade immune attacks. A Ziopharm-supported phase 1 trial that's testing the IL-12 combo with Bristol-Myers Squibb’s PD-1 inhibitor Opdivo in glioblastoma has recently finished enrollment. And a phase 2 study in the same setting has started for a cocktail that includes Sanofi and Regeneron’s PD-1 antibody Libtayo.

The scientists believe the therapy could also be used beyond brain tumors. “We have shown here we can now [regulate] gene expression in humans by using this drug-gene switch combination, and the implication here is that we could use this potentially for a number of different gene therapies, where one wants to regulate the production of a protein to maximum therapeutic effects and minimize side effects,” said Antonio Chiocca of Brigham, the study’s corresponding author, in a video interview.