Oncolytic Adenovirus Delivered by Neural Stem Cells Shows Promise Against Malignant Glioma

By Scott Baltic

July 27, 2021

NEW YORK (Reuters Health) - Treatment with an engineered oncolytic adenovirus delivered by neural stem cells appears feasible and safe in patients with malignant gliomas, according to new research.

The small, first-in-human trial also found signs of anti-tumor activity with the therapy, known as NSC-CRAd-S-pk7, especially in patients with gliomas with unmethylated MGMT promoters, Dr. Maciej Lesniak of Northwestern University Feinberg School of Medicine, in Chicago, and colleagues report.

Earlier work has demonstrated the safety and activity of oncolytic viruses in patients with recurrent gliomas, but the viruses' tumor-targeting ability has been limited by low dissemination and infiltration in tumor tissue, the researchers explain. Neural stem cells (NSCs), however, have been shown to effectively disseminate to target glioma cells.

"The addition of NSC-CRAd-S-pk7 to neurosurgery and chemoradiotherapy showed potential survival benefit in comparison with historical controls," Dr. Lesniak, chair of the department of neurological surgery, and his colleagues write in The Lancet Oncology.

If all goes well, he told Reuters Health by email, NSC-CRAd-S-pk7 could be the next Food and Drug Administration-approved therapy for brain cancer.

The treatment was injected during initial surgery and allowed immediate initiation of standard chemoradiotherapy. Previous research has shown that early use of radiation following surgery and injection of this oncolytic adenovirus, "enhances replication of CRAd-S-pk7 in virus-infected glioma cells," the team notes.

The open-label, dose-escalation phase-1 trial included 12 patients (mean age, 54) with newly diagnosed, resectable, high-grade malignant glioma (WHO grade III or IV), enrolled from 2017 to 2019.

Following surgical resection, each patient received an injection of NSC-CRAd-S-pk7 in up to 10 sites in the wall of the resection cavity. The three doses evaluated were 50 million NSCs carrying 62.5 billion viral particles (three patients), 100 million NSCs carrying 125 billion viral particles (three patients), and 150 million NSCs carrying 187.5 billion viral particles (six patients).

Standard radiotherapy and chemotherapy began 10 to 14 days later. Patients also received low-dose steroids.

Of the 12 patients, cancer progressed in 10, and nine died.

Among the nine patients with glioma containing an unmethylated MGMT promoter, median progression-free survival was 8.8 months, and median overall survival was 18.0 months. "These patients are known to not benefit from temozolomide treatment and exhibit poor prognostic outcomes," the authors note.

Over a median follow-up of 18 months, no deaths were seen from adverse events.

Of six patients receiving the highest dose, one developed a grade-2 subdural fluid collection. A second developed grade-3 meningitis after NSC-CRAd-S-pk7 was inadvertently injected into a ventricle; the patient recovered fully.

In an accompanying editorial, Dr. Juan Fueyo of the Department of Neuro-Oncology at the University of Texas MD Anderson Cancer Center, in Houston, and colleagues, called this an "elegant study (that) opens the door for combined cell-virus treatments and underscores the value of oncolytic viruses as therapies for brain tumours."

Dr. Patrick Y. Wen, director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute, in Boston, told Reuters Health by email, "There is tremendous interest in viral therapies for brain tumors based on their oncolytic effects, synergy with standard therapies, ability to introduce suicide genes, and especially their ability to induce an inflammatory response, potentially converting immunologically 'cold' tumors into 'hot' tumors that may be susceptible to immunotherapies."

He noted, however, that the study population was very highly selected, with only 12 patients enrolled over more than two years, "so the efficacy data has to be evaluated with caution."

"It is virtually impossible to comment on the preliminary efficacy compared to historic data from very different populations," Dr. Wen added.

The study did not have commercial funding.

SOURCE: https://bit.ly/3hFwqPv The Lancet Oncology, online June 29, 2021.