Targeted alpha therapy for recurrent high-grade glioma with [²²⁵Ac]-PSMA: a new theranostic approach.

PURPOSE: To evaluate the feasibility, safety, and preliminary efficacy of systemic targeted alpha therapy with [²²⁵Ac]-PSMA in patients with recurrent high-grade glioma (HGG). Glioblastoma multiforme (GBM) and HGGs are highly aggressive primary brain tumors with limited treatment options at recurrence. Expression of prostate-specific membrane antigen (PSMA) in the neovasculature of GBM provides a promising target for radioligand therapy using alpha emitters such as Actinium-225. METHODS: Four patients with histologically confirmed recurrent HGG received [²²⁵Ac]-PSMA therapy at a dose of 100 kBq/kg per cycle. Diagnoses were established according to the WHO classification available at the time of diagnosis. The cohort included three patients with GBM and one patient with a high-grade diffuse glial tumor, WHO grade III. Treatment cycles were intended at 8-12-week intervals. Baseline and follow-up assessments were performed visually and then semi-quantitave parameters were described on [⁶⁸Ga]-PSMA PET/MRI or PET/CT images also using contrast-enhanced MRI. Clinical status and hematologic parameters were monitored throughout therapy and follow-up. RESULTS: While every patient ultimately developed progressive disease following treatment, the predefined PSMA-avid index lesion regressed in one patient and remained stable in another. No grade ≥ 3 adverse events attributable to [²²⁵Ac]-PSMA or treatment-related mortality were observed. Low-grade toxicity was limited and mainly consisted of mild xerostomia. CONCLUSION: Systemic [²²⁵Ac]-PSMA therapy appeared feasible and well tolerated, showing preliminary evidence of disease control in recurrent HGGs.