December 2015, Vol. 4, No. 6

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Poliovirus Shows Complete Response in Several Glioblastoma Patients

American Society of Gene and Cell Therapy

Mathias,Gromeier98pxIn a role reversal, poliovirus is fast becoming a viable therapy for one of cancer’s deadliest diseases. Researchers at The Preston Robert Tisch Brain Tumor Center at Duke University Medical Center are using engineered poliovirus to treat recurrent glioblastoma—making tumors disappear and extending survival beyond 3 years in some patients.

For a population whose median survival ranges from 6 to 8 months, the results of this phase 1 clinical trial are nothing short of remarkable, and after a CBS 60 Minutes interview with lead researcher Matthias Gromeier, MD, patients from around the world are clamoring to enroll.

“What is remarkable is that we get these types of responses with a single administration of virus without further therapy,” said Gromeier, Associate Professor of Neurosurgery, Molecular Genetics, and Microbiology at Duke University Medical Center.

Gromeier recently discussed this radical approach to treatment at the American Society of Gene and Cell Therapy (ASGCT) annual meeting in New Orleans, LA.

The Hardest Cancer to Treat

Glioblastoma is by all accounts a terrifying disease. Considered by Gromeier “the hardest cancer to treat,” it is uniformly fatal with a prognosis of approximately 14 months.

“The standard of care does not work,” he said. “Tumors always recur, and there is no approved therapy for recurrence. At recurrence, median survival is 6 to 8 months.”

Although the idea of targeting cancer with viruses is hardly new, according to Gromeier, valid strategies involving oncolytic viruses have only recently emerged because of technological advances in genetic engineering.

Details of Treatment

PVS-RIPO is a live attenuated, oral serotype 1 poliovirus vaccine (Sabin vaccine) that contains a heterologous internal ribosomal entry site from human rhino­virus. In other words, researchers removed the inherent disease-causing genetic code from the poliovirus genome and spliced a code from a cold-causing rhinovirus in its place. With these changes, PVS-RIPO can no longer cause poliomyelitis, but because the receptor for poliovirus (CD155), which is used for cell entry, is abnormally present on most tumor cells, it naturally infects almost all cancer cells.

“Poliovirus induces a form of cell death that does not resemble any orchestrated form of demise, such as apoptosis, necrosis, necroptosis,” Gromeier said. “It’s a highly unusual, highly danger-signaling form of death. At the same time, it elicits antiviral immunity or interferon response, so the combining of the danger signals and pathogen signals helps to recruit cytotoxic T cells to recognize these tumor antigens.”

PVS-RIPO is infused directly into a patient’s tumor in the brain via a form of convection-enhanced delivery, which takes advantage of the natural flow of the cerebral spinal fluid. Once inside the tumor, PVS-RIPO infects and kills tumor cells, recruiting the patient’s immune response against the cancer.

Because of its fast-paced life cycle, the poliovirus behaves “more like a toxin than a virus,” explained Gromeier, ultimately producing viral polypeptides that exert a toxic effect.

“This sets up a classic immune effector response against the tumor that we believe is protecting some of our patients durably,” he said.

Responses and Survival

At the 19th Annual Scientific Meeting of the Society for Neuro-Oncology in Miami last November, Gromeier’s team reported phase 1 dose-finding and safety results from 15 patients.

Median survival was 15.2 months, and the 12-month survival rate was 70%; 18- and 24-month survival rates were 43.8% and 29.2%, respectively. Serious adverse events included hemiparesis, intracranial hemorrhage at catheter removal, lymphopenia, seizure, and hyperglycemia, as well as lethargy, headache, diarrhea, paresthesia, and hyperbilirubinemia.

However impressive these results, they fail to convey the full potential of the treatment, exemplified by the first 2 patients treated in the trial. Gromeier elaborated on these outcomes at the ASGCT meeting.

“The first patient we treated had a very large tumor excised. She got a single PVS-RIPO infusion, and 2 months later the tumor was significantly enlarged. The MRIs looked awful, but the patient was doing fine,” he said. “By 6 months we saw glial scarring. By 11 months the tumor had significantly shrunk. And by a year or so, the tumor was gone.”

Three years removed from treatment, the patient is still tumor free. Although she must take anticonvulsants for the rest of her life, she is otherwise completely healthy.

“You would never know this patient had a brain tumor,” Gromeier observed.

The second patient treated, a 71-year-old man with recurrent glioblastoma, also shows a normal MRI 3 years after treatment.

“He recently delivered a 1-hour talk at a fundraiser,” said Gromeier. “The patient’s 74 now, and you would not know that this man had a recurrent glioblastoma.”

Problems with Steroids and Dosing

Despite these early successes, there have been setbacks as researchers continue to modify dose and enrollment criteria. By observing differences related to prior steroid use, researchers concluded that both steroid use and dose of PVS-RIPO were correlated with outcomes.

“We’ve amended our enrollment criteria, and we now exclude patients on high-dose steroids,” Gromeier reported.

Researchers have also lowered the treatment dose to avoid subsequent steroid dependency.

“We can’t leave out steroids entirely because…[they] protect the brain from swelling, but we try to taper the patient off within a week or so. We believe that high doses of steroids are inappropriate because they are too immunosuppressive,” he explained.

Researchers are now treating with “dose level minus 1,” which is 5x10e7 (50 million infectious units) and half the initial starting dose. They have been able to successfully taper steroids in most patients treated with this dose.

At the time of the ASGCT meeting, 2 patients were alive past 3 years and another past 2 years, all of whom were complete responders to the infusion and not steroid dependent.

Although Gromeier is encouraged by the preliminary data, he emphasized that the phase 1 study is still ongoing, and much research remains to be done.

“We have found the dose,” he concluded, “but we haven’t observed the patients long enough to know for sure. We need to wait for another half year to be confident.”

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