Evolocumab as an immunomodulator in glioma: A window of opportunity trial evaluating PCSK9 inhibition to enhance surface MHC-I on tumor

Abstract

AbstractMany cancers, including glioma, evade immunosurveillance by downregulating surface major histocompatibility class (MHC)-I. Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degradation of multiple receptors, including MHC-I and peripheral levels are specifically elevated in glioma (Human Protein Atlas). Inhibition of PCSK9 (PCSK9i) blocks MHC-I degradation. Evolocumab is a PCSK9i monoclonal antibody (mAb) indicated for hyperlipidemia. However, mAbs have limited penetrance across the blood brain/tumor barrier (BBB/BTB). We conducted a non-randomized surgical window-of-opportunity study to evaluate if peripheral evolocumab penetrates the BBB/BTB and effects tumor (PesKE;NCT04937413). 32 patients with newly diagnosed or recurrent glioma were enrolled (M: 16, F: 16; average age of controls: 51.85, evolocumab: 53). Of these, 4 who received evolocumab and 17 control participants had tissue for research. No significant adverse events were reported. However, BBB/BTB penetration (assessed by mass spectroscopy (LC-MS/MS)) was akin to other mAbs, with a tumor:blood ratio of 0.0332 (SD±0.0215) in contrast-enhancing and 0.0112 (SD±0.0039) in non-contrast-enhancing cases. LC-MS/MS analysis of the tumor proteome found a positive, but non-significant, relationship between evolocumab and MHC-I (HLA-A (R2=0.5002, p=0.2928), HLA-B (R2=0.7269, p=0.1474)). A significant negative relationship was observed between tumoral evolocumab and Apolipoprotein E (R2=0.9113, p=0.0454*). Tumor tissue with the highest evolocumab demonstrated increased surface MHC-I and CD8+T cell infiltration (assessed by immunofluorescence and immunohistochemistry). In conclusion, pre-resection evolocumab is well tolerated but exhibits BBB/BTB penetrance akin to other mAbs. However, increased tumoral evolocumab/PCSK9i may enhance MHC-I/CD8+infiltration and reduce ApoE. Future work will explore combining evolocumab with BBB/BTB opening therapies like low-intensity focused ultrasound.One Sentence SummaryWe conducted a tissue-based study in glioma patients to evaluate if peripheral evolocumab enters brain, enhances MHC-I expression, and boosts CD8+T cell tumor infiltration.