A Device that Delivers: Promising DIPG Treatment Route

Diffuse intrinsic pontine glioma (DIPG), a rare pediatric brain tumor, continues to pose a challenge to health care providers due to its difficult anatomic location and lack of effective treatment. The tumor originates on the brain stem, making complete surgical removal unfeasible, and available treatment—radiation and chemotherapy—have only been able to provide temporary response, not a cure.

However, a promising treatment has emerged in the form of Alcyone Lifesciences Inc.’s Alcyone MEMS Cannula (AMC), which is capable of precisely delivering an oncolytic adenovirus (tasadenoturev) directly into the pediatric brain stem tumor.

The oncolytic adenovirus is engineered to replicate specifically in tumor cells with an abnormal retinoblastoma (RB) pathway by infecting cells through integrins, which are more abundant in glioma cells.

The targeted delivery system was created using the company’s microelectromechanical system (MEMS) technology platform. Designed to provide optimal targeted biodistribution and to be easy for neurosurgeons to use, the system utilizes dual micro-channels on the MEMS tip to prevent reflux or back flow along the cannula shaft, which is known to be a drawback with other devices currently available.

With the system, neurosurgeons are able to select a target, navigate the AMC to the target, and observing in real-time the precision delivery of the therapeutic agent under intra-procedural magnetic resonance imaging (MRI) guidance.

In the phase 1, unicentric, non-randomized clinical trial consisting of a small series DIPG patients, investigators at the Clínica Universidad de Navarra reported positive updates with the injected oncolytic adenovirus. Specifically, Sonia Tejada, MD, PhD, neurosurgeon and principal investigator, confirmed the safe administration of the oncolytic adenovirus with use of the AMC device in the brainstem of pediatric patients prior to radiotherapy with minimal side effects.

The data presented at the Biennial International Symposium for Pediatric Neuro-Oncology (ISPNO) in Denver, Colorado, from June 29 to July 3, 2018, were pulled from 12 subjects between the ages of 1 and 18 years who had been newly diagnosed with DIPG, had a lesion considered to be accessible for stereotactic biopsy by the investigator so as to allow injection without virus entrance into the ventricular system, had no previous DIPG treatment, and a Karnofsky/Lanksky performance status score less than or equal to 70 before trial inclusion.

The Karnofsky/Lanksky performance status classifies patients’ level of functional impairment by grading scores from 100 to 0, with lower scores correlating with a worse survival rate for most serious illnesses.

Primary outcomes for the trial included safety, tolerability, and toxicity of DNX-2401 injected in the cerebellar peduncle as well as hematologic and neurologic toxicity as measured in the time frame of 12 weeks after virus injection. Secondary endpoints included overall survival at 12 months (OS12), the percentage of responses, and the induced immune response against the tumor.

Primary measures included the overall survival rate, images response according to the observed complete/partial response evident in MRI, quality of life assessment and any changes over time, and an assessment of a samples collection that included tumor and blood samples for future molecular and immune studies. All primary measures were measured in the time frame of 12 weeks after virus injection.

The oncolytic adenovirus was intratumorally administered following a stereotactic tumor biopsy utilizing the same trajectory after verification of catheter position with intraoperative MRI. Patients also received standard radiotherapy and/or chemotherapy after 3 to 4 weeks. Close monitoring of neurological status, blood tests, and brain MRI were included in the follow up.

"With technical support from Alcyone, Ricardo Diez Valle, MD, PhD, and our neurosurgical team have been able to consistently and safely use the AMC for precision delivery of the oncolytic adenovirus in very difficult to reach brain stem tumors in six pediatric DIPG patients with no observed grade 3 or 4 adverse events,” stated Dr Tejada in a recent statement. “We were pleased to be able to present these early, but promising data at the ISPNO meeting.”

Currently, the estimated primary completion date is August 20, 2019.