Many 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.

KS, MWF, MJV, KMH, COR, EEB, KEB, ELT, DMA, AD, HSF, MOJ, AF, SK, EDB, JEH, REM, EC, GAG, CYL declare that they have no competing interests. JHS reports an equity interest in Istari Oncology, which has licensed intellectual property from Duke related to the use of poliovirus and D2C7 in the treatment of glioblastoma. JHS is an inventor on patents related to Brain Bi-specific T cell Engagers (BRiTE), PEP-CMV DC vaccine with tetanus, as well as poliovirus vaccine and D2C7 in the treatment of glioblastoma. GYL reports consulting fees from Servier Pharmaceuticals. GYL is a consultant for and has equity in SNPsnipe, Inc. APP is a consultant for Sygnomics, Syapse, and Servier Pharmaceuticals, and has an equity in Sygnomics. PEF reports support as an Akash fellow of the CRI Lloyd J. Old STAR award program and has received consulting fees and grant funding from Monteris Medical outside the submitted work. MK reports grants or contracts from BMS, AbbVie, BioNTech, CNS Pharmaceuticals, Daiichi Sankyo Inc., Immorna Therapeutics, Immvira Therapeutics, JAX lab for genomic research, and Personalis, Inc.; received consulting fees from AnHeart Therapeutics, Berg Pharma, George Clinical, Manarini Stemline, and Servier; received honoraria from GSK; and is on a data safety monitoring board for BPG Bio.

NCT04937413

https://clinicaltrials.gov/study/NCT04937413

Knox Martin Foundation, Philanthropic Grant (MK) Langford Cregger Foundation, Philanthropic Grant (MK)

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study received approval by the institutional review board at the Duke Cancer Institute (DCI, Duke IRB# Pro000108375). Study monitoring was performed both internally by the Principal Investigator (PI) and institutionally by the DCI.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Targeted proteomic data have been deposited to the ProteomeXchange Consortium (PXD053215) via the Panorama Public repository.

https://panoramaweb.org/ccb1LM.url