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

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 have limited blood brain/tumor barrier penetrance (BBB/BTB). We conducted a window-of-opportunity trial, evaluating evolocumabs BBB/BTB penetrance and biological effect (PesKE; NCT04937413). Patients with newly diagnosed or 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 a single subcutaneous evolocumab dose pre-procedure, of which 4 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 monoclonals. 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 and untreated controls. Pre- resection evolocumab is well tolerated but exhibits BBB/BTB penetrance akin to other monoclonal antibodies. 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. One Sentence SummaryWe conducted a tissue-based study in glioma patients to evaluate if peripheral evolocumab enters tumors, enhances surface MHC-I, and boosts effector CD8+ T cell infiltration. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/24309192v4_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@a2f9e6org.highwire.dtl.DTLVardef@1c480e8org.highwire.dtl.DTLVardef@1eb18deorg.highwire.dtl.DTLVardef@1adc5f7_HPS_FORMAT_FIGEXP M_FIG C_FIG