Neural stem cell delivery of oncolytic adenovirus feasible in newly diagnosed malignant glioma

A first-in-human, open-label, phase I, dose-escalation trial shows that treatment of newly diagnosed malignant glioma with an engineered oncolytic adenovirus delivered by neural stem cells (NSCs) is feasible and safe.

“Despite aggressive therapy, high-grade malignant gliomas are the most lethal central nervous system [CNS] tumours in adults, with median survival of 14–21 months for newly diagnosed glioblastoma,” wrote the investigators. [N Engl J Med 2005;352:987-996; JAMA 2017;318:2306-2316]

“Oncolytic adenoviral therapy is a promising therapeutic approach in malignant glioma owing to its direct viral oncolytic effects and its ability to elicit an immune response. Nevertheless, oncolytic viruses have poor distribution and spread through the tumour mass, with limited ability to effectively cross the blood–brain barrier [BBB]. On the other hand, neural stem cells [NSCs] have been shown to cross the BBB, distribute within the tumour bed, surround the tumour border, and migrate within the brain parenchyma to target glioma cells, making them a suitable candidate for oncolytic adenovirus delivery,” they explained.

The investigators used a genetically engineered oncolytic virus, CRAd-S-pk7, with enhanced viral replication and targeting of glioma cells, which improved antitumour activity and increased survival in mouse and hamster glioma models. [Sci Transl Med 2013;5:184ra59; Hum Gene Ther 2007;18:589-602] A therapeutic payload of the virus was delivered via NSCs in experimental glioblastoma models and demonstrated a 50 percent increase in median overall survival vs the direct application of CRAd-S-pk7. [J Natl Cancer Inst 2013;105:968-977]

In the current phase I trial, 12 patients (median age, 52 years; female, 58 percent) with WHO grade III–IV glioma were enrolled and received NSC-CRAd-S-pk7 injections into the walls of resection cavity following surgery. Patients in the first cohort received a dose starting at 6.25 × 10¹⁰ viral particles administered by 5.00 × 10⁷ NSCs, those in the second cohort received a dose of 1.25 × 10¹¹ viral particles administered by 1.00 × 10⁸ NSCs, while those in the third cohort received a dose of 1.875 × 10¹¹ viral particles administered by 1.50 × 10⁸ NSCs. Within 10–14 days, treatment with temozolomide and radiotherapy (RT) was initiated. Primary endpoints were safety and toxicity profile and the maximum tolerated dose for a future phase II trial. [Lancet Oncol 2021;22:1103-1114]

One patient receiving the highest prespecified dose of 1.50 × 10⁸ NSCs loading 1.875 × 10¹¹ viral particles developed grade 3 viral meningitis due to the inadvertent injection of NSC-CRAd-S-pk7 into the lateral ventricle. After hospitalization, the patient fully recovered and, subsequently, three additional patients were enrolled at the same dose without major toxicity or complications.

“Most treatment-emergent adverse events [TRAEs] were not related to NSC-CRAd-S-pk7 and all were commonly observed toxicities of subsequent chemotherapy and RT,” wrote the investigators. “The most common grade 3 AEs were decreased lymphocyte count, hypertension, and muscle weakness. No dose-limiting toxicity was noted, and the highest preassigned dose was the maximum tolerated dose.”

Five severe AEs were reported, including a thromboembolic event, encephalopathy, cerebral oedema, muscle weakness, and a case of meningitis described above, which was the only severe AE probably related to NSC-CRAd-S-pk7. All patients recovered fully from their AEs, with no dropouts or deaths due to an AE. “The quality-of-life data were similar to that of the standard treatment in gliomas,” added the investigators.

Assessment of best response showed that of 12 patients, one had a partial response, one had pseudoprogression, and ten had stable disease. Median progression-free survival (PFS) was 9.1 months and median overall survival (OS) was 18.4 months. “The addition of NSC-CRAd-S-pk7 to neurosurgery and chemoradiotherapy showed potential survival benefit in comparison with historical controls,” the investigators highlighted.

In the subset of patients (n=9) with unmethylated MGMT promoter, median PFS was 8.8 months, and median OS was 18.0 months. “NSCCRAd-S-pk7 showed potential survival benefit in patients whose tumours had an unmethylated MGMT promoter, who are known to obtain no benefit from temozolomide treatment and exhibit poor prognostic outcomes,” the investigators noted.

Of the three patients with methylated MGMT promoter, two patients were censored at last follow-up, and the one uncensored patient had a PFS of 24.2 months and an OS of 36.4 months.

“This phase I trial has shown the safety and tolerability of NSC-CRAd-S-pk7 injection during surgery in patients with newly diagnosed malignant gliomas. Immediate initiation of standard chemoradiotherapy was feasible and did not lead to undue delay or complications. Patients had favourable survival outcomes, especially those with unmethylated MGMT promoter. This trial sets the stage for a phase II/II study, in which the efficacy of NSC-CRAd-S-pk7 in prolonging survival in a larger cohort of patients with controlled conditions can be explored,” concluded the investigators.