Abstract
Many cancers evade immunosurveillance by downregulating surface major histocompatibility class (MHC)-I. Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes MHC-I degradation and is elevated in glioma. Evolocumab is a clinically approved PCSK9 inhibitor, which restores MHC-I expression in pre-clinical cancer models. However, monoclonal antibodies (mAbs) have limited blood brain/tumor barrier penetrance (BBB/BTB). The aim of this window-of-opportunity trial was to evaluate evolocumab’s BBB/BTB penetrance and biological effect in glioma (PesKE; NCT04937413). Patients with newly diagnosed/recurrent glioma undergoing a clinically indicated biopsy or resection were enrolled (n=32, M: 16, F: 16; control average age: 51.85, evolocumab: 53). Intervention participants (n=6) received subcutaneous evolocumab 4-14 days pre-procedure. 4/6 intervention participants provided research tissue. No significant adverse events were observed. Evolocumab was detected in all analyzed intervention tissue, with an average tumor:blood ratio of 0.0222 (SD±0.0190), akin to other mAbs. Evolocumab quantitation was 4.44x greater in contrast-enhancing (mean 0.0068 fmol/mcg (SD±0.001)) vs non-contrast enhancing cases (mean 0.0015 fmol/mcg (SD±0.0004)). Proteomic analysis found positive trends between evolocumab and MHC-I subtypes (HLA-A-C, E-G), with a significant positive correlation with HLA-H (R2=0.9584, p=0.021*). Tumor tissue with higher evolocumab titers demonstrated increased surface MHC-I and CD8+ T cell infiltration. Increased CD8+ TNF, FASLG and GZMA transcription was observed in high titer tissue compared to low titer tissue/untreated controls. Pre-resection evolocumab is well tolerated but exhibits BBB/BTB penetrance akin to other mAbs. Increased tumoral evolocumab/PCSK9i may enhance tumoral MHC-I/effector CD8+ infiltration. Future work will explore combining evolocumab with BBB/BTB opening therapies like low-intensity focused ultrasound.