Neoadjuvant cabozantinib restores CD8 T cells in patients with locally advanced non-metastatic clear cell renal cell carcinoma: a phase 2 trial

Neoadjuvant cabozantinib restores CD8 T cells in patients with locally advanced non-metastatic clear cell renal cell carcinoma: a phase 2 trial | 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 Neoadjuvant cabozantinib restores CD8 T cells in patients with locally advanced non-metastatic clear cell renal cell carcinoma: a phase 2 trial Haydn Kissick, Mehmet Bilen, BaoHan Vo, Yuan Liu, Rachel Greenwald, and 27 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4849400/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Cabozantinib is an oral multikinase inhibitor approved for treatment in metastatic renal cell carcinoma (RCC). We hypothesized that neoadjuvant cabozantinib could downstage localized tumors, facilitating partial nephrectomy, and facilitating surgery in patients with locally advanced tumors that would require significant adjacent organ resection. We, therefore, conducted a phase 2, single-arm trial of cabozantinib treatment for 12 weeks in 17 patients with locally advanced biopsy-proven non-metastatic clear cell RCC before surgical resection. Six patients (35%) experienced a partial response, and 11 patients (65%) had stable disease. We identified that plasma cell-free DNA (cfDNA), VEGF, c-MET, Gas6, and AXL were significantly increased while VEGFR2 decreased during cabozantinib treatments. There was a trend towards CD8+ T cells becoming activated in the blood, expressing the proliferation marker Ki67 and activation markers HLA-DR and CD38. Cabozantinib treatment depleted myeloid populations acutely. Importantly, immune niches made up of the stem-like CD8+ T cells and antigen presenting cells were increased in every patient. These data suggest that cabozantinib treatment was clinically active and safe in the neoadjuvant setting in patients with locally advanced non-metastatic clear cell RCC and activated the anti-tumor CD8+ T cell response. The trial is registered at ClinicalTrials.gov under registration no. NCT04022343. Biological sciences/Immunology/Tumour immunology Biological sciences/Cancer/Urological cancer/Renal cancer/Renal cell carcinoma Health sciences/Oncology/Cancer/Urological cancer/Renal cancer/Renal cell carcinoma Full Text Additional Declarations Yes there is potential Competing Interest. M.A.B. has acted as a paid consultant for and/or as a member of the advisory boards of Exelixis, Bayer, BMS, Eisai, Pfizer, AstraZeneca, Janssen, Calithera Biosciences, Genomic Health, Nektar, EMD Serono, SeaGen, and Sanofi and has received grants to his institution from Merck, Xencor, Bayer, Bristol-Myers Squibb, Genentech/Roche, SeaGen, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Exelixis, Nikang, Loxo Oncology, Ambrx, Regeneron, Acrivon Therapeutics, Amgen, Genome & Company, AAA, Peloton Therapeutics, and Pfizer for work performed as outside of the current study. The other authors declare no competing interests. Supplementary Files SupplementaryTable.xlsx Table 1 - 11 SupplementaryInformation.pdf Cite Share Download PDF Status: Under Review 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-4849400","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":336810950,"identity":"40ca20ec-e6df-44ea-8bb9-7b8ffa733eda","order_by":0,"name":"Haydn Kissick","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9ElEQVRIiWNgGAWjYBACAyCWYGBI4GFgYGxgbKiAibMRreUMCVrAHMbGNiK0mLOfMbxdwJAmI99/uPHjzHk20fzSZwwYPpQdxqnFsifH2HoGQw6PwY3EZsmN29JyZ/blGDDOOIdbi8GBHDNpHoYKHgMJxjbGh9sO5244w2PAzNuGR8v5NxAt8v0HgVrm/Ido+YtPyw2wLTk8DAcS2xg3NhyAaGHEq+VZsTWPQRrELzOOJefO7GErONhzLh2Pw5I33uapSLaX7z/+8GNPjV1uPw/zxgc/yqxxamFg4DCAxA6yyAE86oGA/QFhkVEwCkbBKBjZAACzyVXpglUU5AAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-7624-5598","institution":"Emory University","correspondingAuthor":true,"prefix":"","firstName":"Haydn","middleName":"","lastName":"Kissick","suffix":""},{"id":336810951,"identity":"4b8ff48b-1683-4791-a2d7-71e510f75fb9","order_by":1,"name":"Mehmet Bilen","email":"","orcid":"","institution":"Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University","correspondingAuthor":false,"prefix":"","firstName":"Mehmet","middleName":"","lastName":"Bilen","suffix":""},{"id":336810952,"identity":"c863210b-574b-4053-a337-6393d37532a3","order_by":2,"name":"BaoHan Vo","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"BaoHan","middleName":"","lastName":"Vo","suffix":""},{"id":336810953,"identity":"f5a0b7cf-0953-422e-9d12-368e8c19e15e","order_by":3,"name":"Yuan Liu","email":"","orcid":"https://orcid.org/0000-0001-8926-3058","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Yuan","middleName":"","lastName":"Liu","suffix":""},{"id":336810954,"identity":"8241b05f-ce11-4fdd-bdb3-a1bbcab6672d","order_by":4,"name":"Rachel Greenwald","email":"","orcid":"https://orcid.org/0000-0003-3139-5079","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Rachel","middleName":"","lastName":"Greenwald","suffix":""},{"id":336810955,"identity":"4eeb81dc-1d8f-46ae-8031-68e5ebbc13d8","order_by":5,"name":"Amir Davarpanahfakhr","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Amir","middleName":"","lastName":"Davarpanahfakhr","suffix":""},{"id":336810956,"identity":"25cb98e5-1f95-49af-b2ed-8243c74ca3ef","order_by":6,"name":"Donal McGuire","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Donal","middleName":"","lastName":"McGuire","suffix":""},{"id":336810957,"identity":"63c873ea-f6b4-4a92-bc1f-e9c8123394a2","order_by":7,"name":"Rakesh Shiradkar","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Rakesh","middleName":"","lastName":"Shiradkar","suffix":""},{"id":336810958,"identity":"5f952e6e-282d-4b71-b771-af86c646fbe1","order_by":8,"name":"Liping Li","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Liping","middleName":"","lastName":"Li","suffix":""},{"id":336810959,"identity":"9d289fc3-b915-4b56-93dc-09fb79088156","order_by":9,"name":"Bassel Nazha","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Bassel","middleName":"","lastName":"Nazha","suffix":""},{"id":336810960,"identity":"c381065b-2a32-4990-91d6-826cd9c4822b","order_by":10,"name":"Jacqueline Brown","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Jacqueline","middleName":"","lastName":"Brown","suffix":""},{"id":336810961,"identity":"2c13a265-b7fc-4eef-89a2-b5b9347eb59f","order_by":11,"name":"Sierra Williams","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Sierra","middleName":"","lastName":"Williams","suffix":""},{"id":336810962,"identity":"0a947c8b-6824-478a-9d4b-6f2c70bae824","order_by":12,"name":"Wilena Session","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Wilena","middleName":"","lastName":"Session","suffix":""},{"id":336810963,"identity":"5611c8da-4ab9-4383-a1ce-1d39df23f82b","order_by":13,"name":"Greta Russler","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Greta","middleName":"","lastName":"Russler","suffix":""},{"id":336810964,"identity":"efbbc8ff-6bae-4e8d-8068-7f593dfd0b3e","order_by":14,"name":"Sarah Caulfield","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Sarah","middleName":"","lastName":"Caulfield","suffix":""},{"id":336810965,"identity":"11bb0ddf-ad4f-4df4-b9ad-50475a81d1ba","order_by":15,"name":"Shreyas Joshi","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Shreyas","middleName":"","lastName":"Joshi","suffix":""},{"id":336810966,"identity":"4aa39858-a8fc-4679-a1fb-f50dc4756629","order_by":16,"name":"Vikram Narayan","email":"","orcid":"https://orcid.org/0000-0003-3731-4209","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Vikram","middleName":"","lastName":"Narayan","suffix":""},{"id":336810967,"identity":"27574c3d-2c3f-4df0-9a8f-953254bff50a","order_by":17,"name":"Christopher Filson","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Christopher","middleName":"","lastName":"Filson","suffix":""},{"id":336810968,"identity":"27399a07-c023-434d-8471-141be7a41289","order_by":18,"name":"Kenneth Ogan","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Kenneth","middleName":"","lastName":"Ogan","suffix":""},{"id":336810969,"identity":"26ccd715-41a2-4c57-ac13-2989333d5d8a","order_by":19,"name":"Omer Kucuk","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Omer","middleName":"","lastName":"Kucuk","suffix":""},{"id":336810970,"identity":"1634f794-185c-4862-b895-8e62c6b41c16","order_by":20,"name":"Bradley Carthon","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Bradley","middleName":"","lastName":"Carthon","suffix":""},{"id":336810971,"identity":"98e2327f-1826-44ed-ad32-e984f8deb5ee","order_by":21,"name":"Luke del Balzo","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Luke","middleName":"del","lastName":"Balzo","suffix":""},{"id":336810972,"identity":"df3d4410-7a59-4ba0-8c31-95b19ec300ad","order_by":22,"name":"Athena Cohen","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Athena","middleName":"","lastName":"Cohen","suffix":""},{"id":336810973,"identity":"57a2dd61-4af5-411c-8278-4aedc56e5174","order_by":23,"name":"Adriana Boyanton","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Adriana","middleName":"","lastName":"Boyanton","suffix":""},{"id":336810974,"identity":"70da987f-5d9a-4cc0-8a82-f0714fdbde25","order_by":24,"name":"Nataliya Prokhnevska","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Nataliya","middleName":"","lastName":"Prokhnevska","suffix":""},{"id":336810975,"identity":"82d28293-3489-4c3c-a056-f56557f64daa","order_by":25,"name":"Maria Cardenas","email":"","orcid":"https://orcid.org/0000-0002-8566-9576","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"","lastName":"Cardenas","suffix":""},{"id":336810976,"identity":"19d248fc-bd18-4d67-a40b-6a5bdec0d749","order_by":26,"name":"Ewelina Sobierajska","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Ewelina","middleName":"","lastName":"Sobierajska","suffix":""},{"id":336810977,"identity":"69c9d972-68c6-4cb2-84d6-cee453da5c67","order_by":27,"name":"Caroline Jansen","email":"","orcid":"https://orcid.org/0000-0001-9128-2004","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Caroline","middleName":"","lastName":"Jansen","suffix":""},{"id":336810978,"identity":"9fae9d22-68d8-42b4-8831-b3dba53d7904","order_by":28,"name":"Dattatraya Patil","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Dattatraya","middleName":"","lastName":"Patil","suffix":""},{"id":336810979,"identity":"1c6bec07-9911-493b-8450-b1e1b0232349","order_by":29,"name":"Nicaise Edouard","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Nicaise","middleName":"","lastName":"Edouard","suffix":""},{"id":336810980,"identity":"2d1cdec1-cb54-4cbd-896d-ff85585aca10","order_by":30,"name":"Adeboye Osunkoya","email":"","orcid":"https://orcid.org/0000-0001-5712-8134","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Adeboye","middleName":"","lastName":"Osunkoya","suffix":""},{"id":336810981,"identity":"fc67fadb-ead9-45f8-9afc-30f55ce8dcdb","order_by":31,"name":"Viraj Master","email":"","orcid":"","institution":"Emory University","correspondingAuthor":false,"prefix":"","firstName":"Viraj","middleName":"","lastName":"Master","suffix":""}],"badges":[],"createdAt":"2024-08-02 15:20:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4849400/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4849400/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":61985009,"identity":"c6c59259-bd0f-4782-a3b4-171ab6ec40cf","added_by":"auto","created_at":"2024-08-08 00:29:45","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":20001854,"visible":true,"origin":"","legend":"","description":"","filename":"MainManuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4849400/v1_covered_28bc3cec-97db-491f-8c3f-8ae8575107fd.pdf"},{"id":61984674,"identity":"cc158641-cedc-4d97-8808-209cc2fc6011","added_by":"auto","created_at":"2024-08-08 00:21:30","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":119366,"visible":true,"origin":"","legend":"Table 1 - 11","description":"","filename":"SupplementaryTable.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4849400/v1/6fe5d335125be7d75b6a016a.xlsx"},{"id":61984675,"identity":"9a80d3b1-3884-41bd-a050-1d95303a5d8a","added_by":"auto","created_at":"2024-08-08 00:21:31","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":2439767,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"SupplementaryInformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4849400/v1/00e3d13034124759e8865257.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nM.A.B. has acted as a paid consultant for and/or as a member of the advisory boards of Exelixis, Bayer, BMS, Eisai, Pfizer, AstraZeneca, Janssen, Calithera Biosciences, Genomic Health, Nektar, EMD Serono, SeaGen, and Sanofi and has received grants to his institution from Merck, Xencor, Bayer, Bristol-Myers Squibb, Genentech/Roche, SeaGen, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Exelixis, Nikang, Loxo Oncology, Ambrx, Regeneron, Acrivon Therapeutics, Amgen, Genome \u0026 Company, AAA, Peloton Therapeutics, and Pfizer for work performed as outside of the current study. The other authors declare no competing interests.","formattedTitle":"Neoadjuvant cabozantinib restores CD8 T cells in patients with locally advanced non-metastatic clear cell renal cell carcinoma: a phase 2 trial","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4849400/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4849400/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Cabozantinib is an oral multikinase inhibitor approved for treatment in metastatic renal cell carcinoma (RCC). We hypothesized that neoadjuvant cabozantinib could downstage localized tumors, facilitating partial nephrectomy, and facilitating surgery in patients with locally advanced tumors that would require significant adjacent organ resection. We, therefore, conducted a phase 2, single-arm trial of cabozantinib treatment for 12 weeks in 17 patients with locally advanced biopsy-proven non-metastatic clear cell RCC before surgical resection. Six patients (35%) experienced a partial response, and 11 patients (65%) had stable disease. We identified that plasma cell-free DNA (cfDNA), VEGF, c-MET, Gas6, and AXL were significantly increased while VEGFR2 decreased during cabozantinib treatments. There was a trend towards CD8+ T cells becoming activated in the blood, expressing the proliferation marker Ki67 and activation markers HLA-DR and CD38. Cabozantinib treatment depleted myeloid populations acutely. Importantly, immune niches made up of the stem-like CD8+ T cells and antigen presenting cells were increased in every patient. These data suggest that cabozantinib treatment was clinically active and safe in the neoadjuvant setting in patients with locally advanced non-metastatic clear cell RCC and activated the anti-tumor CD8+ T cell response. The trial is registered at ClinicalTrials.gov under registration no. NCT04022343.","manuscriptTitle":"Neoadjuvant cabozantinib restores CD8 T cells in patients with locally advanced non-metastatic clear cell renal cell carcinoma: a phase 2 trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-08 00:21:26","doi":"10.21203/rs.3.rs-4849400/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-cancer","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"natcancer","sideBox":"Learn more about [Nature Cancer](http://www.nature.com/natcancer/)","snPcode":"","submissionUrl":"","title":"Nature Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"a33bfc37-16df-4347-a671-1c1d0d9cc35f","owner":[],"postedDate":"August 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":35675618,"name":"Biological sciences/Immunology/Tumour immunology"},{"id":35675619,"name":"Biological sciences/Cancer/Urological cancer/Renal cancer/Renal cell carcinoma"},{"id":35675620,"name":"Health sciences/Oncology/Cancer/Urological cancer/Renal cancer/Renal cell carcinoma"}],"tags":[],"updatedAt":"2025-01-29T15:35:24+00:00","versionOfRecord":[],"versionCreatedAt":"2024-08-08 00:21:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4849400","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4849400","identity":"rs-4849400","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}