Oncolytic Adenovirus for Malignant Glioma: Feasibility and Safety

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In a first-in-human phase I trial reported in The Lancet Oncology, Fares et al found that neural stem cell delivery of an oncolytic adenovirus (NSC-CRAd-S-pk7) was safe and feasible in patients with newly diagnosed malignant glioma, with immunologic and histopathologic findings supporting continued evaluation of NSC-CRAd-S-pk7 in this setting.

Study Details

The trial enrolled 12 patients from Northwestern Memorial Hospital (primary site) and City of Hope National Medical Center between April 2017 and November 2019. After neurosurgical resection, NSC-CRAd-S-pk7 was injected into the walls of the resection cavity. Increasing doses were administered in three cohorts:

  • Cohort 1 (n = 3) received 6.25 × 1010 viral particles administered by 5.00 × 10⁷ neural stem cells
  • Cohort 2 (n =3) received 1.25 × 10¹¹ viral particles administered by 1.00 × 10⁸ neural stem cells
  • Cohort 3 (n = 6) received 1.875 × 10¹¹ viral particles administered by 1.50 × 10⁸ neural stem cells.

Treatment with temozolomide and radiotherapy was initiated within 10 to 14 days.

Key Findings

Histopathologic evaluation showed that 11 patients (92%) had glioblastoma and 1 (8%) had anaplastic astrocytoma. At the time of analysis (March 2021), median follow-up was 18 months (interquartile range = 14–22 months). No formal dose-limiting toxicity was reached, with 1.50 × 10⁸ neural stem cells administering 1.875 × 10¹¹ viral particles being the recommended phase II dose.

The most common grade 3 adverse events were decreased lymphocyte count (42%), hypertension (42%), muscle weakness (33%), and hyponatremia (25%); two grade 4 events occurred in one patient. Two patients had NSC-CRAd-S-pk7–related toxicities: one developed grade 2 subdural fluid collection, and the other developed grade 3 viral meningitis due to the inadvertent injection of NSC-CRAd-S-pk7 into the lateral ventricle. There were no treatment-related deaths.

Assessment of best response showed that 1 patient (8%) had partial response, 1 (8%) had pseudoprogression, and 10 (83%) had stable disease. Magnetic resonance imaging showed a decrease in contrast enhancement and peritumoral hyperintensity around the resection cavity after treatment. Median progression-free survival was 9.1 months (95% confidence interval [CI] = 8.5 months–not reached), and median overall survival was 18.4 months (95% CI = 15.7 months–not reached).  

Histopathologic analysis in patients who underwent repeat surgical resection at the time of disease progression showed decreased expression of survivin and syndecan-1 after NSC-CRAd-S-pk7 treatment. As noted by the investigators, higher survivin expression has been associated with temozolomide resistance and worse overall survival, and syndecan-1 expression is associated with advanced tumor progression and poor prognosis. They observed that the decreases in survivin and syndecan-1 expression might be due to the replication of CRAd-S-pk7 in the glioma cells, leading to programmed cell death.

Assessment of early immune response showed an increase in inflammatory myeloid recruitment—eg, increased neutrophil and monocyte ratios—at higher doses, followed by a decline in these ratios and an increase in absolute lymphocyte count 14 days after surgery. In cohort 3, an increase in circulating lymphocytes, particularly CD8+ T cells, was observed at 14 days; the CD8+ T cells in the tumor microenvironment were found to be active and cytotoxic, as indicated by an increase in CD8+:CD4+ ratio and increased expression of the early activation marker CD69 showing recent activation and tissue infiltration.

The investigators concluded, “NSC-CRAd-S-pk7 treatment was feasible and safe. Our immunological and histopathological findings support continued investigation of NSC-CRAd-S-pk7 in a phase II/III clinical trial.”

Maciej S. Lesniak, MD, of the Department of Neurological Surgery, Northwestern University, Feinberg School of Medicine, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the National Institutes of Health. For full disclosures of the study authors, visit

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