CD22-CAR T cell multiomic features linked to patient outcomes in CD19-CAR resistant large B cell lymphoma

CD22-CAR T cell multiomic features linked to patient outcomes in CD19-CAR resistant large B cell lymphoma | 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 CD22-CAR T cell multiomic features linked to patient outcomes in CD19-CAR resistant large B cell lymphoma Matthew Frank, Anne Marijn Kramer, Tara Murty, Kameron Rodrigues, and 22 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7706791/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 More than half of patients with relapsed/refractory large B-cell lymphoma experience disease progression after CD19-directed chimeric antigen receptor (CAR19) T-cell therapy. We investigated CAR22 therapy in 38 patients with CAR19-refractory disease, achieving 68% overall response rate (ORR) and 53% complete response rate (CR)(NCT04088890). Long-term follow-up (median 43.5 months), revealed sustained clinical benefit among complete responders, who achieved a median progression-free survival of 52 months and a 75% estimated 3-year overall survival rate. Using multi-omics analyses, we identified that intrinsic T-cell stemness characteristics present at apheresis associated with therapeutic success. Responding patients exhibited elevated TCF7 and LEF1 transcription factor activity and enhanced chromatin accessibility at TCF/LEF binding motifs. CAR T-cell products from CR patients demonstrated higher T-cell receptor diversity. Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) was associated with interferon-stimulated gene expression and STAT2 activity. These findings challenge the paradigm that T cells are irreversibly compromised after CAR therapy failure and provide mechanistic insights for optimizing sequential CAR therapies. Health sciences/Medical research/Translational research Biological sciences/Cancer/Cancer therapy/Cancer immunotherapy Full Text Additional Declarations Yes there is potential Competing Interest. Anne Marijn Kramer: University College London Business and Autolus (Patents & Royalties). Mark Hamilton: Kite Pharma (Consultancy). Hrishikesh Srinagesh: Sobi (Honoraria), Takeda (Honoraria). John Baird: Genentech, Regeneron, Janssen, CARGO Therapeutics (Research Funding); Curio Sciences, Kite/Gilead (Consultancy); Kite/Gilead (Honoraria). Elena Sotillo: Lepton Pharmaceuticals, Galaria (Consultancy); Lyell Immunopharma (Stock Options). Saurabh Dahiya: Kite/Gilead (Consultancy, Research Funding); Bristol Myers Squibb, Adaptive Biotechnologies, Incyte (Consultancy); Kyverna Therapeutics (Research Funding). Lori Muffly: Kite, Autolus Therapeutics (Consultancy, Honoraria); Kite (Research Funding); Adaptive, Vor, Jasper, Wugen (Research Funding); Pfizer, Astellas, Incyte (Consultancy). Crystal Mackall: Astra-Zeneca, Link Cell Therapies, Ensoma, RedTree Venture Capital, Nektar, Immatics, GBMNewCo, Grace Science (Consultancy); CARGO Therapeutics (Consultancy, Patents & Royalties); Tune Therapeutics (Research Funding). David Miklos: Novartis, Kite-Gilead, Biocartis, Eli Lilly, Bristol Myers Squibb, Kyverna, Janssen, Miltenyi, Autolus Therapeutics, Adaptive Biotech (Consultancy); Kite-Gilead, Adicet, Regeneron, Biocartis, Janssen, Fate Therapeutics, Miltenyi, Autolus Therapeutics, Adaptive Biotech, Allogene (Research Funding); Fosun Inc (Honoraria); Stanford University (Employment). Matthew Frank: ADC Therapeutics, Cargo Therapeutics, Allogene Therapeutics, Kite-Gilead, Adaptive Biotechnology (Consultancy); Pepromene Bio, Cargo Therapeutics, Allogene Therapeutics, Kite-Gilead, Adaptive Biotechnology (Research Funding). Supplementary Files Extendeddata.pdf CCT5029 Extended data 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-7706791","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":521213199,"identity":"c758782e-eef7-4b9c-8887-28f7331101f0","order_by":0,"name":"Matthew 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Mark Hamilton: Kite Pharma (Consultancy). Hrishikesh Srinagesh: Sobi (Honoraria), Takeda (Honoraria). John Baird: Genentech, Regeneron, Janssen, CARGO Therapeutics (Research Funding); Curio Sciences, Kite/Gilead (Consultancy); Kite/Gilead (Honoraria). Elena Sotillo: Lepton Pharmaceuticals, Galaria (Consultancy); Lyell Immunopharma (Stock Options). Saurabh Dahiya: Kite/Gilead (Consultancy, Research Funding); Bristol Myers Squibb, Adaptive Biotechnologies, Incyte (Consultancy); Kyverna Therapeutics (Research Funding). Lori Muffly: Kite, Autolus Therapeutics (Consultancy, Honoraria); Kite (Research Funding); Adaptive, Vor, Jasper, Wugen (Research Funding); Pfizer, Astellas, Incyte (Consultancy). Crystal Mackall: Astra-Zeneca, Link Cell Therapies, Ensoma, RedTree Venture Capital, Nektar, Immatics, GBMNewCo, Grace Science (Consultancy); CARGO Therapeutics (Consultancy, Patents \u0026 Royalties); Tune Therapeutics (Research Funding). David Miklos: Novartis, Kite-Gilead, Biocartis, Eli Lilly, Bristol Myers Squibb, Kyverna, Janssen, Miltenyi, Autolus Therapeutics, Adaptive Biotech (Consultancy); Kite-Gilead, Adicet, Regeneron, Biocartis, Janssen, Fate Therapeutics, Miltenyi, Autolus Therapeutics, Adaptive Biotech, Allogene (Research Funding); Fosun Inc (Honoraria); Stanford University (Employment). Matthew Frank: ADC Therapeutics, Cargo Therapeutics, Allogene Therapeutics, Kite-Gilead, Adaptive Biotechnology (Consultancy); Pepromene Bio, Cargo Therapeutics, Allogene Therapeutics, Kite-Gilead, Adaptive Biotechnology (Research Funding).","formattedTitle":"CD22-CAR T cell multiomic features linked to patient outcomes in CD19-CAR resistant large B cell lymphoma","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"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":"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-7706791/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7706791/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"More than half of patients with relapsed/refractory large B-cell lymphoma experience disease progression after CD19-directed chimeric antigen receptor (CAR19) T-cell therapy. We investigated CAR22 therapy in 38 patients with CAR19-refractory disease, achieving 68% overall response rate (ORR) and 53% complete response rate (CR)(NCT04088890). Long-term follow-up (median 43.5 months), revealed sustained clinical benefit among complete responders, who achieved a median progression-free survival of 52 months and a 75% estimated 3-year overall survival rate. Using multi-omics analyses, we identified that intrinsic T-cell stemness characteristics present at apheresis associated with therapeutic success. Responding patients exhibited elevated TCF7 and LEF1 transcription factor activity and enhanced chromatin accessibility at TCF/LEF binding motifs. CAR T-cell products from CR patients demonstrated higher T-cell receptor diversity. Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) was associated with interferon-stimulated gene expression and STAT2 activity. 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