A surgical window of opportunity trial evaluating the effect of the PCSK9 inhibitor evolocumab on tumoral MHC-I expression and CD8+infiltration in glioma
Authors: Singh Kirit , Foster Matthew W. , Violette Marlene J. , Corcoran Anna M. , Hotchkiss Kelly M. , Railton Chelsea O. , Blandford Emily E. , Blethen Kathryn E. , Thomas Elizabeth L. , Ashley David M. , Desjardins Annick , Friedman Henry S. , Johnson Margaret O. , Friedman Allan , Keir Stephen , Buckley Evan D. , Herndon James E. , McLendon Roger E. , Sampson John H. , Calabrese Evan , Lopez Giselle Y. , Grant Gerald A. , Patel Anoop P. , Gregory Simon G. , Li Chuan-Yuan , Fecci Peter E. , Khasraw Mustafa 
Published: June 2024

Background

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).

Method

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.

Results

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,FASLGandGZMAtranscription was observed in high titer tissue compared to low titer tissue/untreated controls.

Conclusions

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.

Key points

PCSK9 promotes MHC-I degradation and is increased in glioma

Evolocumab (PCSK9 mAb inhibitor) exhibits BBB penetrance akin to other mAbs

Tumoral evolocumab titers correlates with tumor cell surface MHC-I expression

Importance of the study

This tissue-based study evaluates the pre-clinical finding that PCSK9 inhibition (PCSK9i) increases cell surface MHC-I expression in the clinical glioma setting. Of note, PCSK9 is specifically elevated in glioma, a tumor which is known for low MHC-I expression and typically possesses few tumor-infiltrating lymphocytes. PCSK9i was achieved by means of a peripherally administered monoclonal antibody (mAb, evolocumab). Though uptake of evolocumab across the blood-brain/tumor barrier (BBB/BTB) was similar to other mAbs, dose-response relationships between intratumoral evolocumab and MHC-I subtypes were observed. Having observed that PCSK9i can induce biological changes within tumor, we will rationalize our approach to explore combination with BBB/BTB opening therapies such as low-intensity focused ultrasound. Window-of-opportunity studies like PesKE demonstrate how tissue-based trials permit rapid evaluation of a drugs pharmacokinetic (PK) and pharmacodynamic (PD) properties in glioma. Here, we find evidence of PD (biological) effect and will now explore combination approaches to enhance PK parameters (tumoral uptake).

Graphical Abstract