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

A surgical window of opportunity trial evaluating the effect of the PCSK9 inhibitor evolocumab on tumoral MHC-I expression and CD8+ infiltration in glioma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article A surgical window of opportunity trial evaluating the effect of the PCSK9 inhibitor evolocumab on tumoral MHC-I expression and CD8 + infiltration in glioma Mustafa Khasraw, Kirit Singh, Matthew Foster, Marlene Violette, and 23 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5822396/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version 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 (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). 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. 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, FASLG and GZMA transcription was observed in high titer tissue compared to low titer tissue/untreated controls. 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. One Sentence Summary: We 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. Biological sciences/Immunology/Tumour immunology Health sciences/Oncology/Cancer/CNS cancer Full Text Additional Declarations Yes there is potential Competing Interest. MWF, MJV, KMH, COR, EEB, KEB, ELT, DMA, AD, HSF, MOJ, AF, SK, EDB, JEH, REM, EC, GAG, SGG, CYL declare that they have no competing interests. KS reports grants paid to his institution and research contracts from Adaptin Bio, which has licensed intellectual property from Duke related to the use of Brain Bi-specific T cell Engagers (BRiTE) and combination autologous lymphocyte therapy. 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. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5822396","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":403872266,"identity":"19af46cf-4645-4ca9-8ca6-e1394f8101b4","order_by":0,"name":"Mustafa 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KS reports grants paid to his institution and research contracts from Adaptin Bio, which has licensed intellectual property from Duke related to the use of Brain Bi-specific T cell Engagers (BRiTE) and combination autologous lymphocyte therapy. 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.","formattedTitle":"\u003cp\u003eA surgical window of opportunity trial evaluating the effect of the PCSK9 inhibitor evolocumab on tumoral MHC-I expression and CD8\u003csup\u003e+\u003c/sup\u003e infiltration in glioma\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5822396/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5822396/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMany 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). 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. 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, FASLG and GZMA transcription was observed in high titer tissue compared to low titer tissue/untreated controls. 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.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOne Sentence Summary: \u003c/strong\u003eWe 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.\u003c/p\u003e","manuscriptTitle":"A surgical window of opportunity trial evaluating the effect of the PCSK9 inhibitor evolocumab on tumoral MHC-I expression and CD8+ infiltration in glioma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-22 04:38:56","doi":"10.21203/rs.3.rs-5822396/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"17682106-d2e4-46cc-9086-7b72f81489f7","owner":[],"postedDate":"January 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":43222740,"name":"Biological sciences/Immunology/Tumour immunology"},{"id":43222741,"name":"Health sciences/Oncology/Cancer/CNS cancer"}],"tags":[],"updatedAt":"2025-05-23T11:55:17+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-22 04:38:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5822396","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5822396","identity":"rs-5822396","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}