Editors' ChoiceDrug Delivery

Convection-enhanced delivery of drugs for deadliest pediatric brain tumors

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Science Translational Medicine  25 Jul 2018:
Vol. 10, Issue 451, eaau7380
DOI: 10.1126/scitranslmed.aau7380


Convection-enhanced delivery in the brainstem of children with tumors is clinically feasible and safe within defined parameters.

Diffuse infiltrative pontine glioma (DIPG) is a rare, incurable brainstem tumor and among the deadliest central nervous system cancers of childhood. There are about 300 new pediatric cases of DIPG diagnosed each year under the age of 10. Devastated family and clinicians are largely helpless because the treatment options are exceptionally scarce with poor outcomes. In a phase 1 clinical trial, Souweidane et al. demonstrated the remarkable safety of a convection-enhanced delivery of radioimmunotherapeutic drug directly into the tumor, therefore avoiding intruding on delicate brainstem tissue or the need to cross the blood-brain barrier (BBB).

The DIPG occurs in one of the most delicate parts of the brainstem called the pons, which relays signals from the forebrain to the cerebellum and controls functions like sleep, respiration, swallowing, blood pressure, and posture. DIPG cannot be safely removed through surgery because of its location and infiltrative nature. Alternatively, radiation and chemotherapy only offer short-term benefits and overall poor outcomes with a median overall survival of less than 12 months. Systemic chemotherapy is frequently ineffective because therapeutics cannot cross the BBB to reach tumor pockets. The clinical research team used a convection-enhanced delivery approach to infuse a radioimmunotherapy agent targeting the surface antigen B7-H3, an immune modulator of natural killer and T cells that is overexpressed in DIPGs. In convection-enhanced delivery, therapeutic agents are locally delivered through catheters placed stereotactically near the tumor or directly within the tumor mass, therefore producing a high local concentration of drugs. The primary endpoint was the identification of the maximum tolerated dose of radioisotope-tagged monoclonal antibody against B7-H3 antigen, administered by convection enhanced delivery. Remarkably, no serious side effects or dose-limiting toxicities were observed in the pediatric patients, who were routinely assessed for adverse events in hospital and at the weekly outpatient visits. Although the study was not powered enough to assess overall survival (only 28 eligible patients) and lacked diagnostic confirmation through tissue sampling, this is the first in-human evidence of clinical feasibility and safety of convection-enhanced delivery of therapeutics. The results could provide a foundation for controlled drug delivery strategies in DIPG and raise the possibility that the approach might also help disease management in disseminated DIPG tumors.

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