乌鸦传媒

Treatment with the novel, genetically modified poliovirus, PVSRIPO, improved survival in patients with recurrent stage IV glioma, a single-center study found.

At 27.6 months follow-up, the median overall survival (OS) among 61 patients treated with PVSRIPO was 12.5 months (95% CI 9.9-15.2) compared with 11.3 months (95% CI 9.8-12.5) in a historical control group treated at the same institution, reported Darell Bigner, MD, PhD, of Duke University Medical Center in Durham, North Carolina, and colleagues.

At 2 years a plateau in the survival curve emerged in the PVSRIPO-treated group, while in the control group it continued to decline. The rate of OS was 21% at both 2 and 3 years with PVSRIPO compared with 14% and 4%, respectively, in the control group.

"There is no standard of care treatment for glioblastoma once it recurs," Bigner told 乌鸦传媒. "Most studies have a median survival of less than a year, and there are no really good therapeutic options with long-term survivors, such as we have seen in the poliovirus study."

Two patients remained alive at more than 5 years following treatment.

The research was presented Tuesday at the International Conference on Brain Tumor Research and Therapy in Solstrand, Norway and published simultaneously in the .

Eight patients had durable radiographic responses at data cutoff (March 20, 2018). There were two complete responses, with the patients alive at over 70.4 months and 15.1 months following PVSRIPO treatment. Three had stable to partial responses of 60 months, 34 months, and 26 months. And three were treated with a short course of bevacizumab (Avastin), and were without signs of active tumor and need for additional treatment at over 34.1 months, 27.1 months, and 15.4 months each following PVSRIPO treatment.

PVSRIPO is a live attenuated poliovirus based on the Sabin vaccine strain, developed by researchers at Duke and modified to reduce the chance of replication. With the CD155 receptor expression increased on glioblastoma cells, the poliovirus gains entry into these cells while being more likely to bypass healthy cells. And genetic alterations in PVSRIPO prevent replication in healthy cells even if reached by the virus. The treatment received in May 2016.

The investigators could not identify factors to explain why some patients benefited from treatment while others did not. "We have done DNA sequencing of the tumors of about a third of the patients, and the patients that respond best had the lowest gene mutational load," Bigner said. "We are trying to figure out the mechanism of that."

"The data are very promising," Hideho Okada MD, PhD, of the University of California San Francisco, told 乌鸦传媒. Okada, who was not involved in the study, highlighted some of the unique challenges in treating recurrent glioblastoma:

• Invasive growth through the brain
• Poor penetration of therapeutics to the glioblastoma, especially where the tumor infiltrates into healthy brain tissue where the blood-brain barrier is intact
• Profound immunosuppression
• Chemotherapy and radiotherapy resistance

Outside of the current study there are a number of under examination. Okada, who is also involved in , said that he and his fellow researchers hope these novel "approaches, especially in combinations, may allow us to overcome the challenges" associated with the treatment of glioblastoma.

The current study was a phase I dose-escalation trial that enrolled 61 consecutive patients with recurrent, World Health Organization grade IV malignant glioma from 2012 to 2017. Patients ages ≥18 years and with a Karnofsky Performance Score of 70% or greater were included. All were vaccinated with the polio vaccine prior to commencing treatment.

Administration is a relatively simple neurosurgical procedure, said Bigner, who is also a co-founder of the company that developed PVSRIPO. "The virus is administered directly into the tumor itself," he said. A catheter tube is placed in the tumor and the virus is infused. "It is a very simple closed surgical procedure with simply a small burr hole made in the skull."

Seven doses were evaluated in the dose-escalation, and then dose-expansion phase -- from 10⁷ to 10¹⁰ 50% tissue-culture infectious doses (TCID₅₀). One dose-limiting toxicity, a grade 4 intracranial hemorrhage following catheter removal, occurred in a patient who received dose level 5 (10¹⁰ TCID₅₀). The identified phase II dose was level -1 (5.0 × 10⁷ TCID₅₀).

The historical control group was comprised of 104 patients treated at Duke over the last 10 years. Bigner said that these patients "met the exact enrollment criteria for the poliovirus trial," but had been treated with the best available therapies at the time, prior to the availability of PVSRIPO.

"Much more needs to be learned, but the clinical results to date encourage further exploration of this new treatment approach," wrote Dan Longo, MD, and Lindsey Baden, MD, both of the Dana-Farber Cancer Institute in Boston, in an accompanying .

But they raised a number of questions regarding the use of viral approaches to cancer treatment: "How will local administration interact with systemic immunity such that lesions that are remote from the injection site will be recognized and eliminated?" they stated. "How will the presence or absence of pretreatment immunity to the virus affect the efficacy?"

Longo and Baden also questioned whether there could be dangers related to restoring viral pathogenicity: "Should a destruct gene (a gene that allows the virus to be killed by a chemotherapy agent) be inserted to control an unexpected expansion of the virus?"