A phase 0/surgical window-of-opportunity study in progress, evaluating evolocumab in patients with high-grade glioma or glioblastoma.

TPS2076 Background: High-grade gliomas (HGGs) are immunologically ‘cold’ tumors. This phenomenon is partly due to reduced expression of major histocompatibility class (MHC) I on the surface of tumor cells, which prevents CD8+ cytotoxic T lymphocyte activity (CTLs). Blockade of proprotein convertase subtilisin/kexin type 9 (PCSK9) increases MHC class I expression, enhances CTL tumoral infiltration, and potentiates checkpoint inhibition in vivo. Evolocumab is an FDA-approved fully human IgG2 monoclonal antibody PCSK9 inhibitor which is clinically indicated for hyperlipidemia. This study seeks to determine whether evolocumab can cross the blood-brain barrier (BBB) and enhance MHC I expression on resected tumor cells, serving as a potential future adjunct for immunotherapy. Methods: This study will enroll ten patients over 18 years who have newly diagnosed or recurrent HGG. These patients will also need to be undergoing resection of their tumor as part of their planned treatment pathway. Following informed consent, patients will receive evolocumab (420mg, subcutaneously) 7-14 days before surgical debulking of the tumor. We will collect tissue which is not required for histological tumor analysis and compare it with a contemporaneous matched control cohort. This will consist of resected tumor specimens from patients not treated with evolocumab. Quantification of the drug will be performed using mass spectroscopy, flow cytometry, and single-cell sequencing. The primary objective of this study is to evaluate whether evolocumab can cross the BBB and be measured in resected tumor specimens taken from patients with HGG. Secondary objectives include an analysis of lipid metabolism and MHC-I expression on the tumor via flow cytometry and CITEseq. Wilcoxon rank-sum test or a two-sample t-test, will compare groups for these endpoints. Exploratory analyses will determine if evolocumab leads to changes in tumorigenic pathways and the immune profile of tumor infiltrating lymphocytes (TILs). Bioinformatic analyses will be performed using protein set enrichment, gene ontology (GO) annotations, and search tools from the retrieval of interactive genes/proteins (STRING). Progress: The study was activated on 10/04/2021 (NCT04937413) and at the time of submission has enrolled 5 participants (4 to control arm, 1 to intervention arm). Clinical trial information: NCT04937413.