ASCO: Ziopharm's IL-12 gene therapy boosts survival in hard-to-treat brain cancer

Radiation, chemotherapy and surgery don’t cut it against glioblastoma, an aggressive type of brain cancer that often recurs with a vengeance. Ziopharm is working on a “remote-controlled” gene therapy to buy these patients more time—and early data show it extended patients’ lives by more than a year.

The company tested the treatment, dubbed Controlled IL-12, in 95 patients as a monotherapy in two studies and in combination with a PD-1 inhibitor in a third study. After finding that the treatment worked best in six patients who took low doses of dexamethasone—a steroid commonly prescribed after brain tumor removal surgery—Ziopharm tested it in that exact patient population, adding 36 patients in an expansion study. The treatment helped those patients live a median of 16.2 months, an improvement on the 12.7-month survival rate from the “main” trial, which tested the treatment in 38 patients who took varying amounts of the steroid.

“Sixteen months is very, very encouraging,” Ziopharm CEO Laurence Cooper, M.D., Ph.D., told FierceBiotech. “Those four months may not sound like a lot to me and you, but those four months might represent getting to a wedding or a graduation. Frankly, those four months are 30% more life,” he added, referring to historical survival rates for glioblastoma, which top out at 12 months but could be as short as six months.

A substudy testing Controlled IL-12 with Bristol Myers Squibb’s Opdivo is still in its early days, but signs are encouraging, with half of the patients still alive an average of 8.3 months into treatment. And that’s not all—investigators found that one patient in each study had their tumors shrink, bringing the total partial responses across the three studies to five.

“Observing responses in brain tumors in the setting of recurrence is unusual and highly encouraging, and, along with the survival data, highlight the potential of [Controlled IL-12] for the treatment of [recurrent glioblastoma],” said Antonio Chiocca, M.D., Ph.D., a trial investigator and professor of neurosurgery at Harvard Medical School.

Some patients did exceptionally well, with one patient in the “main” study still responding after nearly two years and one patient from the expansion study still responding after 48 weeks. Cooper thinks the studies may turn up more “exceptional responders,” which could help the company figure out why some patients do better than others and, eventually, help it develop drugs that boost survival even more.

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Glioblastoma has been so hard to tackle because it’s a heterogeneous tumor: “It’s not one set of malignant cells, but really a population of cells that all have different attributes relating to the genetics of the disease,” Cooper said. A treatment may take out some of those tumor cells but leave the rest alone.

“One of the things that’s appealing about IL-12 is that it’s a weapon that activates T cells,” Cooper said.

Controlled IL-12 combines an IL-12 gene therapy with Ziopharm’s pill, veledimex, which can switch the gene therapy on and off as well as tune it up and down. Patients received one dose of veledimex before undergoing surgery to remove their brain tumor. During the surgery, adenovirus vectors that carry the IL-12 gene were injected directly into the tumors. The patients then took veledimex, which turns on IL-12 production in the tumors, waving down T cells to attack and destroy the cancerous tissue.

It’s an ideal approach, Cooper said, because the T cells act like “little cellular scalpels,” eating away at the tumor—even tendrils of it that have penetrated normal brain tissue, beyond the borders where a surgeon can safely operate.

Veledimex is a crucial piece of the puzzle because of how powerful IL-12 is.

“Protein IL-12 has been delivered systemically through intravenous injections back in the day, but the side effects were intolerable because IL-12 activated the immune system globally,” Cooper said. “The trick to harnessing IL-12 is to be able to regulate it rather than giving it to the whole body and hope the patient survives that encounter.”

Even though Ziopharm’s gene therapy is delivered directly to brain tumors, it is “inevitable” that IL-12 will “seep out into circulation,” Cooper said. And that’s where the switch comes in.

“If we get a call, say, from Chicago saying a patient has a fever and impending cytokine storm, we can guide the treating physician from Boston to hold off on the next morning’s dose. And that typically takes care of the problem. The fever goes away and we can restart the veledimex,” he said.

Next up, Ziopharm is looking forward to the Opdivo data maturing. It will also finish enrolling a phase 2 study combining its treatment with Sanofi and Regeneron’s PD-1 blocker Libtayo in the first half of this year, despite the COVID-19 pandemic, Cooper said.

“Looking ahead, we will have a continuum of data readouts this year and into next year, showing survival and MRI imaging of the monotherapy and in combination,” he added. “[They will] allow the company to make a decision about the phase 3 trial. With a sizable cohort of patients about the study, we’ll be able to sit back and say, look: Where do we think we can develop and prove this is a drug?”