Key Points
- Sonodynamic therapy was safe and well-tolerated across multiple energy levels in nine patients with recurrent high-grade gliomas.
- Focused ultrasound successfully activated the sonosensitizer in tumor tissue, with evidence of treatment-associated oxidative stress and tumor cell death in targeted regions.
High-grade gliomas, especially glioblastoma (GBM) and others, remain among the most aggressive brain cancers, with few effective treatment options after the tumor recurs. Even with maximal surgical resection, radiotherapy, and chemotherapy, outcomes are poor, underscoring the need for noninvasive, tumor-specific strategies that can spare healthy tissue.
An Early Clinical Trial of 5-ALA Sonodynamic Therapy in Recurrent High-Grade Glioma
Neurosurgeons have long used 5-aminolevulinic acid (5-ALA) to help visualize tumor cells, because it preferentially accumulates in malignant tissue. Sonodynamic therapy (SDT) builds on that concept and uses focused ultrasound to activate 5-ALA-derived compound within the tumor, generating reactive oxygen species that can damage and kill tumor cells.
Results from a first-in-human clinical trial (NCT04559685) using Insightec’s Exablate Neuro magnetic resonance-guided focused ultrasound (MRgFUS) device and SonALAsense’s intravenous 5-ALA formulation were recently published in Science Translational Medicine.
This phase of the ongoing study, which is being led by Nadar Sanai, MD, chief of neurosurgical oncology at the Barrow Neurological Institute’s Ivy Brain Tumor Center in Phoenix, Arizona, was designed to evaluate the safety, feasibility, pharmacokinetics, and pharmacodynamics of SONALA-001(intravenous 5-ALA) when activated with MRgFUS.
Ten participants were enrolled in the dose-escalation arm of the study, each with recurrent high-grade glioma after prior standard-of-care therapy that included surgical resection, adjuvant chemotherapy, and concurrent radiotherapy. Participants were assigned to receive MRgFUS energy doses of 200, 400, or 800 Joules after infusion of the 5-ALA. Four days after the intervention, the tumors were re-resected. Approximately 50% of the tumor volume was targeted with MRgFUS, while the remainder served as an internal control, enabling direct within-patient comparisons.
Investigators reported no serious drug- or device-related adverse events, supporting that the approach was safe and well-tolerated across the energy levels studied. Post-treatment resection was performed in 9 of the 10 participants, allowing tissue-level assessment of treatment effects. Analyses were performed on both gadolinium enhancing and non-enhancing regions. Evidence of treatment-associated oxidative stress and modest cell death was observed primarily in the enhancing regions. One plausible explanation is that lower concentrations of 5-ALA reached non-enhancing tumor regions, limiting activation of downstream oxidative stress markers. Further studies are needed to optimize the dose of 5-ALA and the focused ultrasound parameters for sonodynamic therapy to assess clinical benefit.
“Our study provides crucial proof-of-principle evidence for the safety and feasibility of 5-ALA sonodynamic therapy as a novel therapeutic modality for recurrent high-grade glioma,” said Dr. Sanai. “Ongoing and future efforts will now focus on optimizing the treatment parameters for clinical efficacy as we advance toward our singular goal to discover new treatments for GBM and other incurable brain tumors.”
The authors concluded that the study showed proof of concept for using SDT in humans. They suggested next steps to optimize treatment parameters for clinical efficiency.
This clinical trial was funded by the Barrow Neurological Institute.
See Science Translational Medicine
For Patients
Enrollment is now closed for this clinical trial. See the study website to learn more or visit clinialtrials.gov.
Four additional clinical trials that are funded or partly funded by the Foundation and using 5-ALA with SDT to treat high-grade gliomas are ongoing or being planned at the following worldwide locations:
- Milan, Italy, at Fondazione IRCCS Istituto Neurologico Carlo Besta (See Clinical Trial of Sonodynamic Therapy for Glioblastoma Begins in Milan)
- London, United Kingdom, at Imperial College Healthcare NHS Trust
- Charlottesville, Virginia, USA, at the University of Virginia (See First Participant Receives Sonodynamic Therapy for Glioblastoma in New Clinical Trial).
- Dallas, Texas, at University of Texas Southwestern Medical Center
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