A surgical window of opportunity trial evaluating the effect of the PCSK9 inhibitor evolocumab on tumoral MHC-I expression and CD8+ infiltration in glioma

Kirit Singh; Matthew W Foster; Marlene J Violette; Anna M Corcoran; Kelly M Hotchkiss; Chelsea O Railton; Emily E Blandford; Kathryn E Blethen; Elizabeth L Thomas; William C McIntosh; David M Ashley; Annick Desjardins; Henry S Friedman; Margaret O Johnson; Allan Friedman; Stephen Keir; Evan D Buckley; James E Herndon; Roger E McLendon; John H Sampson; Evan Calabrese; Giselle Y López; Gerald A Grant; Anoop P Patel; Simon G Gregory; Chuan-Yuan Li; Peter E Fecci; Mustafa Khasraw

doi:10.1038/s41598-025-21064-9

A surgical window of opportunity trial evaluating the effect of the PCSK9 inhibitor evolocumab on tumoral MHC-I expression and CD8⁺ infiltration in glioma

Sci Rep. 2025 Oct 23;15(1):37112. doi: 10.1038/s41598-025-21064-9.

Authors

Kirit Singh^{1

2}, Matthew W Foster³, Marlene J Violette³, Anna M Corcoran^{1

2}, Kelly M Hotchkiss^{1

2}, Chelsea O Railton^{1

2}, Emily E Blandford^{1

2}, Kathryn E Blethen^{1

2}, Elizabeth L Thomas^{1

4}, William C McIntosh^{1

2}, David M Ashley¹, Annick Desjardins¹, Henry S Friedman¹, Margaret O Johnson¹, Allan Friedman^{1

2}, Stephen Keir¹, Evan D Buckley⁵, James E Herndon^{6

5}, Roger E McLendon^{1

2

4}, John H Sampson⁷, Evan Calabrese⁸, Giselle Y López^{1

2

4}, Gerald A Grant^{1

2}, Anoop P Patel^{1

2}, Simon G Gregory^{1

2}, Chuan-Yuan Li⁹, Peter E Fecci^#⁷, Mustafa Khasraw^#^{10

11}

Affiliations

¹ The Preston Robert Tisch Brain Tumor Center, Duke University, Box 3624, Durham, NC, 27710, USA.
² Department of Neurosurgery, Duke University, Durham, NC, USA.
³ Duke Proteomics and Metabolomics Core Facility, Duke University, Durham, NC, USA.
⁴ Department of Pathology, Duke University, Durham, NC, USA.
⁵ Duke Cancer Institute Biostatistics, Duke University, Durham, NC, USA.
⁶ Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA.
⁷ University of Colorado Anschutz Medical Campus, Boulder, CO, USA.
⁸ Department of Radiology, Duke University, Durham, NC, USA.
⁹ Adjunct Professor in the Department of Dermatology, Duke University, Durham, NC, USA.
¹⁰ The Preston Robert Tisch Brain Tumor Center, Duke University, Box 3624, Durham, NC, 27710, USA. mustafa.khasraw@duke.edu.
¹¹ Department of Neurosurgery, Duke University, Durham, NC, USA. mustafa.khasraw@duke.edu.

^# Contributed equally.

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 have limited blood brain/tumor barrier penetrance (BBB/BTB). We conducted a window-of-opportunity trial, evaluating evolocumab's 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 4.44× 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.

Publication types

Clinical Trial, Phase I

MeSH terms

Adult
Aged
Antibodies, Monoclonal, Humanized* / administration & dosage
Antibodies, Monoclonal, Humanized* / pharmacokinetics
Antibodies, Monoclonal, Humanized* / pharmacology
Blood-Brain Barrier / drug effects
Blood-Brain Barrier / metabolism
Brain Neoplasms* / drug therapy
Brain Neoplasms* / immunology
Brain Neoplasms* / pathology
Brain Neoplasms* / surgery
CD8-Positive T-Lymphocytes* / drug effects
CD8-Positive T-Lymphocytes* / immunology
Female
Glioma* / drug therapy
Glioma* / immunology
Glioma* / pathology
Glioma* / surgery
Histocompatibility Antigens Class I* / analysis
Histocompatibility Antigens Class I* / metabolism
Humans
Lymphocytes, Tumor-Infiltrating / drug effects
Lymphocytes, Tumor-Infiltrating / immunology
Male
Middle Aged
PCSK9 Inhibitors* / administration & dosage
PCSK9 Inhibitors* / pharmacokinetics
PCSK9 Inhibitors* / pharmacology
Proprotein Convertase 9 / metabolism

Substances

Antibodies, Monoclonal, Humanized
evolocumab
Histocompatibility Antigens Class I
PCSK9 Inhibitors
PCSK9 protein, human
Proprotein Convertase 9