[⁶⁸Ga]Ga-PSMA PET/MRI, histological PSMA expression and preliminary experience with [¹⁷⁷Lu]Lu-PSMA therapy in relapsing high-grade glioma

Purpose: High-grade gliomas (HGG) are still associated with a dismal prognosis. Prostate specific membrane antigen (PSMA) is discussed as a theranostic target for PSMA-directed radioligand therapy ([¹⁷⁷Lu]Lu-PSMA RLT). Here, we report on the correlation of [⁶⁸Ga]Ga-PSMA uptake with histological PSMA expression and on our preliminary experience with [¹⁷⁷Lu]Lu-PSMA RLT in relapsing HGG.

Methods: Patients with relapsing HGG underwent [⁶⁸Ga]Ga-PSMA PET/MRI to evaluate eligibility for an individualized treatment approach with [¹⁷⁷Lu]Lu-PSMA. Standard uptake values (SUV) for tumor and liver and respective tumor-to-background ratios (compared to the liver) (TBR) on [⁶⁸Ga]Ga-PSMA PET/MRI were assessed. Eligibility criteria for [¹⁷⁷Lu]Lu-PSMA therapy were exhaustion of all standard treatment options available and TBR_max>1.0. In 11 samples, immunohistochemical PSMA expression was determined, quantified using the H-score and correlated with uptake on [⁶⁸Ga]Ga-PSMA PET/MRI.

Results: We included 20 patients with a median age of 53 years (IQR 42-57). The median SUV on [⁶⁸Ga]Ga-PSMA PET/MRI was 4.5 (3.7-6.2) for SUV_max and 1.4 (1.1-1.7) for SUV_mean. The respective TBR was maximum 0.6 (0.4-0.8) and mean 0.3 (0.2-0.4). High TBR_max correlated with increased endothelial PSMA expression [H-score of 65 (62.5-77.5)]. Three patients (15%) presented a TBR_max>1.0 and qualified for [¹⁷⁷Lu]Lu-PSMA RLT. No treatment related toxicity was observed.

Conclusion: Only a minority of patients with relapsing HGG qualified for [¹⁷⁷Lu]Lu-PSMA RLT. Our data demonstrates that PSMA expression in the neo-vasculature corresponds to PSMA uptake on [⁶⁸Ga]Ga-PSMA PET/MRI and might be used as a screening tool for patient selection. Future prospective studies need to focus the debate on TBR_max thresholds as inclusion criteria for PSMA RLT.