PGY-5 Neurosurgery Resident Barrow Neurological Institute Phoenix, Arizona, United States
Disclosure(s):
Charuta G. Furey, MD: No financial relationships to disclose
Introduction: 5-aminoleveulinic acid sonodynamic therapy (5-ALA SDT) is a first-in-class drug-device therapeutic that targets the metabolic liabilities of heme biosynthesis in glioblastoma (GBM). Systemic administration of 5-ALA leads to selective protoporphyrin IX (PpIX) accumulation within tumor cells. Preclinical models show that activation of PpIX, a potent sonosensitizer, by non-invasive, non-ablative transcranial magnetic resonance-guided focused ultrasound (MRgFUS) induces oxidative stress and tumor cell death. Here, we present our first-in-human experience evaluating the safety, feasibility, and biological consequences of 5-ALA SDT in recurrent glioblastoma (rGBM) patients (NCT04559685).
Methods: Patients with rGBM undergoing planned resection received 10mg/kg of IV 5-ALA six hours prior to SDT. Patients were assigned to one of three MRgFUS energy levels (200J/400J/800J) four days prior to planned surgical resection. 50% of each patient’s enhancing and non-enhancing tumor was targeted with SDT, with the untreated half serving as an internal control. The primary endpoint was to identify the Optimal Biological Dose – the SDT energy level associated with the maximal tumor cell death.
Results: Nine patients were enrolled and treated across all energy levels (200-800J). None experienced device- or drug-related adverse events. Biomarkers of oxidative stress, including glutathione, thiols, cysteine, and 4-hydroxyonenal, were elevated in treated tissue relative to internal control. SDT-treated GBM tissue also demonstrated increased cleaved caspase-3-mediated apoptosis relative to control, with the effect most pronounced at 200J. No off-target histopathologic or radiographic effects were detected in any patient.
Conclusion : 5-ALA-sonodynamic therapy is safe in rGBM patients and this first-in-human trial suggests 200J as the Optimal Biological Dose. In vivo tissue data indicate that SDT-induced tumor cell death is mediated by targeted oxidative stress, providing the first evidence for proof-of-mechanism in glioblastoma patients.
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